Sodium-coupled monocarboxylate transporter 1 (i.e., SMCT1) and
sodium-coupled monocarboxylate transporter 2
Sodium-coupled monocarboxylate transporter 2 (i.e., SMCT2, also termed SLC5A12) is a plasma membrane transport protein in the solute carrier family. It transports sodium cations (i.e., Na+) in association with the anionic forms (see conjugated ba ...
(i.e., SMCT2) are
plasma membrane
The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
transport proteins
A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...
in the
solute carrier family
The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO ...
. They transport
sodium
Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
cations
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
in association with the
anionic
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
forms (see
conjugated base) of certain
short-chain fatty acids
Short-chain fatty acids (SCFAs) are fatty acids of two to six carbon atoms. The SCFAs' lower limit is interpreted differently, either with one, two, three or four carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, ...
(i.e., SC-FAs) through the plasma membrane from the outside to the inside of cells. For example, propionic acid (i.e., ) in its anionic "propionate" form (i.e., ) along with sodium cations (i.e., Na
+) are co-transported from the
extracellular fluid
In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 50–60% (range 45 to 75%) of total body weight; women and the obese typically ha ...
into a SMCT1-epxressing cell's
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
.
Monocarboxylate transporters The monocarboxylate transporters, or MCTs, are a family of proton-linked
plasma membrane transporters that carry molecules having one carboxylate group (monocarboxylates), such as lactate, pyruvate, and ketones across biological membranes. Acetate ...
(MCTs) are also transport proteins in the solute carrier family. They co-transport the anionic forms of various compounds into cells in association with
proton
A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...
cations (i.e. H
+).
Four of the 14 MCTs, i.e.
SLC16A1
Monocarboxylate transporter 1 is a ubiquitous protein that in humans is encoded by the ''SLC16A1'' gene (also known as MCT1). It is a proton coupled monocarboxylate transporter.
Biochemistry
Detailed kinetic analysis of monocarboxylate transport ...
(i.e., MCT1),
SLC16A7 (i.e., MCT22),
SLC16A8 (i.e., MCT3), and
SLC16A3
Monocarboxylate transporter 4 (MCT4) also known as solute carrier family 16 member 3 is a protein that in humans is encoded by the ''SLC16A3'' gene.
Northern and western blotting and EST database analyses showed MCT4 to be widely expressed and e ...
(i.e., MCT4), transport some of the same SC-FAs anions that the SMCTs transport into cells.
SC-FAs do
diffuse
Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...
into cells independently of transport proteins but at the levels normally occurring in tissues far greater amounts of the SC-FAs are brought into cells that express a SC-FA transporter.
The human SMCT1 and SMCT2 proteins are commonly referred to by the names of the genes responsible for their production, i.e., SLC5A8 and SLC5A12, respectively.
The human gene for SMCT1, i.e., the ''SLC5A8'' gene, is located at position 23.1 on the "q" (i.e., long) arm of
chromosome 12
Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
(notated as 12q23);
SMCT2's gene, i.e., the ''SLC5A12'' gene, is located at position 14.2 on the "p" (i.e., short) arm of
chromosome 11
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...
(notated as chromosome 11p14.2)
The SMCT1 and SMCT2
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s consist of 618(https://www.uniprot.org/uniprotkb/Q8N695/entry) and 618
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s, respectively, and have 57% identity at the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
level.
(The animal proteins are, like the human proteins, here termed SMCT1 and SMCT2 while their genes are termed ''Slc8a5'' and ''Slc5a12'', respectively.) Compared to SMCT1, there have been far fewer reported studies on SMCT2.
SC-FAs come from two sources: the diet and, perhaps more importantly, their release from intestinal bacteria. The intestinal SC-FAs diffuse into the intestine/s wall, enter SMCT1-bearing cells, and diffuse into the blood. These SA-FAs serve as energy sources for cells located in the intestinal wall and throughout the body.
The absorbed SC-FAs also stimulate various functions in cells throughout the body that express one of the SC-FA
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...
, i.e.,
free fatty acid receptor 2,
free fatty acid receptor 3, or
hydroxycarboxylic acid receptor 2
Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the ''HCAR2'' gene and in rodents by the ''Hcar2'' gene. The human ''HCAR2'' gen ...
. (For the functions elicited by SC-FA's activation of these receptors see
free fatty acid receptor 2 functions,
free fatty acid receptor 3 functions, and
hydroxycarboxylic acid receptor 2 functions.)
SMCT1 thereby functions to take up intestinal SC-FAs that have nutritional and wide-ranging stimulating effects.
SMCT1 has other functions. SMCT1-expressing cells in the kidney
and
salivary glands
The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of Duct (anatomy), ducts. Humans have three paired major salivary glands (Parotid gland, parotid, Submandibular gland, submandibula ...
retrieve the SC-FAs in the urine and
saliva
Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...
, respectively, which otherwise would be wastefully discarded. Furthermore, the SC-FAs that enter cells can activate
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
pathways which elicit cellular responses independently of the three cited SC-FA receptors.
This appears to the mechanism underlying the ability of high SMCT1 levels in kidney cells to ameliorate
diabetic kidney disease.
It may also underlie the apparent ability of high SMCT1 levels to suppress the development and/or progression of
breast
The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
,
pancreas
The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
,
lung
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
,
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
,
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
,
stomach
The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...
,
prostate
The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
, and
head & neck cancers. However, these anti-cancerous effects are based primarily on studies finding that, compared to the normal cells in the tissues of these cancers, the cancer cells expressed lower levels of the
messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
(i.e., mRNA) that directs formation of the SMCT1 protein. Most of these studies did not measure the levels of SMCT1 protein but rather inferred their levels based on their SMCT1 mRNA levels.
Studies have shown that the relation between the level of a mRNA and its protein can vary greatly, i.e., that SMCT1 mRNA levels are not always good indicators of SMCT1 protein levels.
This and discrepant findings in studies on colon and pancreas cancers indicate that the role of SMCT1 protein in these cancers requires further investigations.
Cells and tissues expressing SMCT1
The cells and tissues that express SMCT1 mRNA and/or protein include:
enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase ...
s (i.e.,
simple columnar epithelial cells
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
) in the
ilium and
colon of humans, mice,
and rats;
skeletal muscle
Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
of mice;
kidney
brush border cells in the S2 and S3 sections of the straight
proximal tubules
The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...
and cells in the
medulla
Medulla (Latin for "marrow") or medullary may refer to:
Science
* Medulla oblongata, a part of the brain stem
* Renal medulla, a part of the kidney
* Adrenal medulla, a part of the adrenal gland
* Medulla of ovary, a stroma in the center of the ...
of mice, rats, rabbits,
and humans;
cells in the
salivary glands
The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of Duct (anatomy), ducts. Humans have three paired major salivary glands (Parotid gland, parotid, Submandibular gland, submandibula ...
of mice;
neurons
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
in various areas of mouse and rat brains and the astrocytes in rat brains;
and cells in the
ganglion cell layer
In the anatomy of the eye, the ganglion cell layer (ganglionic layer) is a layer of the retina that consists of retinal ganglion cells and displaced amacrine cells.
The cells are somewhat flask-shaped; the rounded internal surface of each rest ...
,
inner nuclear layer
In the anatomy of the eye, the inner nuclear layer or layer of inner granules, of the retina, is made up of a number of closely packed cells, of which there are three varieties: bipolar cells, horizontal cells, and amacrine cells.
Bipolar cell ...
,
inner plexiform layer
The inner plexiform layer is an area of the retina that is made up of a dense reticulum of fibrils formed by interlaced dendrites
A dendrite (from Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that ex ...
,
outer plexiform layer
The outer plexiform layer (external plexiform layer) is a layer of neuronal synapses in the retina of the eye. It consists of a dense network of synapses between dendrites of horizontal cells from the inner nuclear layer, and photoreceptor cell ...
,
photoreceptor inner segments, and
retinal pigment epithelium
The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigment
A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), ...
in the eyes of mice.
As indicated in the cancer studies described below, humans, mice, rats, and/or rabbits express SMCT1 mRNA and/or protein in their normal breast, pancreas, lung, brain, thyroid, stomach, prostate, and certain head & neck tissues.
Agents transported by or blocking SMCT1
The SC-FAs that SMCT1 transfers into cells include the anionic forms of
butyric,
proprionic,
lactic,
acetic,
pyruvic acid
Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an metabolic intermediate, intermediate in several m ...
,
and
β-hydroxybutyric acids.
SMCT1 also transfers the anionic forms of
nicotinic acid
Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan.
Nicotinic acid is also a prescription medication. Amounts f ...
,
the cyclic
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
pyroglutamic acid
Pyroglutamic acid (also known as PCA, 5-oxoproline, pidolic acid) is a ubiquitous but understudied natural amino acid derivative in which the free amino group of glutamic acid or glutamine cyclizes to form a lactam. The names of pyroglutamic acid ...
,
benzoic acid
Benzoic acid () is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. The benzoyl group is often abbreviated "Bz" (not to be confused with "Bn," which ...
,
and pharmacological and therapeutic drugs such as
dichloroacetic acid
Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the organic compound with formula . It is an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. Like the ...
,
bromopyruvic acid
Bromopyruvic acid is the organic compound with the formula BrCH2COCO2H. This colorless solid is the brominated derivative of pyruvic acid. It bears structural similarity to lactic acid and pyruvic acid. It has been investigated as a metabolic p ...
,
Mesalazine
Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is a medication used to treat inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is generally used for mildly to moderately severe disease. I ...
(also termed 5-aminosalicylic acid),
salicylic acid
Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a active metabolite, metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been lis ...
,
and
β-hydroxy β-methylbutyric acid.
This transfer is an electrogenic
cotransporter
Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They ...
process in which at least two Na
+ cations and one
carboxylate
In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an anion, an ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,... ...
-containing anionic compound pass into a cell.
SMCT2 similarly transfers the cited SC-FAs acids into cells but its affinity for them is less than SMCT1's.
Nonsteroidal anti-inflammatory drugs A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents.
List of nonsteroidal steroid receptor mod ...
such as
ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It can be taken oral administration, ...
,
ketoprofen
Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the body's production of prostaglandin.
It was patented in 1967 and approved for medi ...
, and
fenoprofen
Fenoprofen, sold under the brand name Nalfon among others, is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been ...
bind to but are not transported by SMCT1. However, their binding blocks the binding and thereby transportation of the anionic SC-FAs and, presumably, the other anionic compounds that SMTC1 normally transports into cells.
(Hereafter, the acid names of the agents transported by SMCT1 will be used with the understanding that it is their anionic forms which actually enter cells.)
Functions of SMCT1
Gastrointestinal tract
Bacteria in the
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
generate and release various SC-FAs, e.g., butyric, propionic, lactic, acetic,
and β-hydroxybutyric acids.
The SC-FAs released by these bacteria as well as those in the host's diet
diffuse
Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...
into the intestine's wall where they are transported into cells that express SMCT1.
The SMCT1-expressing cells are located in the
intestinal epithelium
The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorptio ...
from the distal end of the
small intestine
The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
down to the distal end of the colon.
Studies in rodents and humans indicate that the transported SC-FAs: 1) are metabolized for
energy
Energy () is the physical quantity, quantitative physical property, property that is transferred to a physical body, body or to a physical system, recognizable in the performance of Work (thermodynamics), work and in the form of heat and l ...
by the endothelial cells and stimulate certain
white blood cells
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
) in the intestinal walls; 2) diffuse into the
portal vein
The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approxima ...
system and enter liver cells which use them for energy or convert them to longer-chain fatty acids for storage;
and 3) pass from the liver to the
systemic circulation
In vertebrates, the circulatory system is a organ system, system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of ...
where they serve as energy for and regulate a wide range of functions in cells that express one of the three SC-FA receptors described above.
Kidney
In one study, SMTC1 mRNA was detected in the kidney
cortex
Cortex or cortical may refer to:
Biology
* Cortex (anatomy), the outermost layer of an organ
** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain''
*** Motor cortex, the regions of the cerebral cortex i ...
's
proximal tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...
s and
medulla
Medulla (Latin for "marrow") or medullary may refer to:
Science
* Medulla oblongata, a part of the brain stem
* Renal medulla, a part of the kidney
* Adrenal medulla, a part of the adrenal gland
* Medulla of ovary, a stroma in the center of the ...
of mice and in the kidney
brush border
A brush border (striated border or brush border membrane) is the microvillus-covered surface of simple cuboidal and simple columnar epithelium found in different parts of the body. Microvilli are approximately 100 nanometers in diameter and th ...
of rabbits.
Vesicles
Vesicle may refer to:
; In cellular biology or chemistry
* Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane
* Synaptic vesicle
In a neuron, synaptic vesicles (or neurotransmitter vesicles) s ...
isolated from the kidney's brush borders of rabbits actively incorporated lactic acid and based on indirect studies other SC-FAs, e.g., acetic, propionic, and butyric acids.
A second study detected SMTC1 protein as well as mRNA in the kidney cortex, tubules, and medulla of mice. This study also showed that mice lacking SMCT1 due to the knockout of their ''Slc8a5'' gene had massive increases in the levels of lactic acid in their urine. This study indicates that SMCT1 protein is essential for the kidney to absorb lactic acid and presumably other SC-FAs from the urine in mice.
The absorption of SC-FAs from the urine is suggested to be an alternative energy source for the kidney cells especially during times of stress.
However, the ''Slc8a5'' gene knockout study in mice did not detect any kidney damage.
In further studies, SMTC1 protein was detected in the brush borders of the proximal convoluted tubules in kidney biopsy specimens taken from patients with diabetic kidney disease; the level of SMCT1 protein in the kidney biopsies of these patients was 78.6% lower than that in the biopsies of the normal renal tissues from patients with kidney cancer (this cancer was considered to be incidental to the analysis). The study also found that in a murine model of
streptozotocin
Streptozotocin or streptozocin ( INN, USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain can ...
-induced
type 2 diabetes
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
and associated
diabetic kidney disease: 1) type 2 diabetic mice (i.e. T2D mice) had lower kidney levels of SMCT1 mRNA than control mice; 2) T2D mice that had the ''Slc5a8'' gene in their
renal tubules
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ...
knocked out
A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
and therefore lacking SMCT1 protein developed far more severe kidney disease than T2D mice that did not have this gene knocked out; 3) T2D mice transfected with an adeno-associated viral vector containing the ''Slc5a'' gene expressed higher levels of SMCT1 and showed marked improvements in their kidney disease; 4) T2D mice treated with oral
1,3-butanediol
1,3-Butanediol is an organic compound with the formula CH3CH(OH)CH2CH2OH, not to be confused with 1,4 Butanediol. With two alcohol functional groups, the molecule is classified as a diol. The compound without the R (or D) designation is racemic, ...
(which the liver converts to β-hydroxybutyric acid) showed less damaged kidneys than untreated mice;
and 5) a study of 100 patients with diabetes found that the higher their blood
serum acetic acid or butyric acid levels were the less likely they were to have diabetes-associated kidney disease.
These findings indicate that lower kidney SMTC1 levels are associated with more severely damaged kidneys in mice and humans with T2D diabetes; 1,3-butanediol, which is converted to the SC-FA, β-hydroxybutyric acid, ameliorated diabetes-associated kidney disease in mice;
and diabetic humans with higher serum levels of acetic or butyric acid were less likely to have diabetes-associated kidney disease.
The study suggested that future studies should be conducted to determine if treating diabetic humans with SC-FAs reduces their chances of developing and/or is an effective treatment for the kidney damage associated with diabetes.
Salivary glands
A study showed that SMTC1 protein is expressed by cells in the
intercalated ducts and
acini
An acinus (; : acini; adjective, acinar or acinous) refers to any cluster of cells that resembles a many-lobed "berry", such as a raspberry (''acinus'' is Latin for "berry"). The berry-shaped termination of an exocrine gland, where the secret ...
of the
parotid
The parotid gland is a major salivary gland in many animals. In humans, the two parotid glands are present on either side of the mouth and in front of both ears. They are the largest of the salivary glands. Each parotid is wrapped around the ...
and the acini of the
submandibular salivary glands of mice. Compared to normal mice, ''Slc5a8'' gene knockout mice had significantly higher levels of lactic acid in their
saliva
Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...
when evaluated with a
pilocarpine
Pilocarpine, sold under the brand name Pilopine HS among others, is a lactone alkaloid originally extracted from plants of the Pilocarpus genus. It is used as a medication to reduce pressure inside the eye and treat dry mouth. As an eye drop ...
-induced salivation test. These findings indicate that the SMCT1 in salivary gland cells mediates the reabsorption of the lactic acid and probably other SC-FAs from the saliva in mice.
This relationship appears similar to that found for the kidney's uptake of urinary SC-FAs.
Skeletal muscle
The function of SMCT1 in the skeletal muscle cells of mice has not been studied but is suggested to have a role in their handling of lactic acid. Resting skeletal muscle cells actively take up lactic acid and use it as an energy source. SMCT1 may contribute to the delivery of this energy source to these cells.
Colitis
In a murine model of dextran sulfate sodium-induced
inflammatory colitis
Colitis is swelling or inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and ...
, ''Slc5a8'' gene knockout and control mice were feed a diet that reduced the levels of SC-FAs in their intestines. The ''Slc5a8'' gene knockout mice developed far more severe colitis and higher numbers of potentially
premalignant
A precancerous condition is a condition, tumor or lesion involving abnormal cells which are associated with an increased risk of developing into cancer. Clinically, precancerous conditions encompass a variety of abnormal tissues with an increase ...
colon
polyps
A polyp in zoology is one of two forms found in the phylum Cnidaria, the other being the medusa. Polyps are roughly cylindrical in shape and elongated at the axis of the vase-shaped body. In solitary polyps, the aboral (opposite to oral) en ...
than control mice. This difference was less pronounced in mice that were fed a normal diet. These findings indicate that 1) the absorption of intestinal SC-FAs suppresses colon inflammation and polyp formation in this mouse model primarily under conditions of low intestinal levels of SC-FAs; 2) in order to suppress colitis in this mouse model, SMCT1 is required when intestinal levels of SC-FAs are low;
and 3) the absorption of SC-FAs when their intestinal levels are normal may involve in addition to SMCT1 other SC-FAs transporters.
Several studies have reported that humans with the
ulcerative colitis
Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...
or
Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
forms of colitis have reduced intestinal numbers of SC-FA-producing bacteria and thereby reduced levels of SC-FAs compared to healthy individuals.
A recent study reviewed the published
controlled trials
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
that used probiotics (which raise the intestinal levels of SC-FAs) to treat ulcerative colitis. The study found with low certainty of evidence that the probiotics increased the rate of clinical remissions and improved patients' clinical symptoms. The magnitudes of these responses were similar to those achieved by a drug commonly used to treat ulcerative colitis, 5‐aminosalicylic acid. The use of this drug in combination with a probiotic appeared to increase remission rates above those achieved with either agent alone.
Another study evaluated two control trials conducted on a small number of patients (i.e., 46 adults). It reported that
probiotic
Probiotics are live microorganisms that provide health benefits when consumed, generally by improving or restoring the microbiota in the gut. Probiotics are considered generally safe to consume, but may cause bacteria– host interactions ...
s did not produce higher remission rates in patients with Crohn's disease.
However, a panel of experts appointed by the
British Dietetic Association
The British Dietetic Association (BDA) is a trade union for dietitians in the United Kingdom. It was founded in 1936 and became a certified union in 1982. It is affiliated to the Trades Union Congress and the Scottish Trades Union Congress.
H ...
analyzed 356 patients randomized to take a probiotic and 311 randomized to take a
placebo
A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials ...
. The panel concluded that patients with mildly active Krohn's disease who took a probiotic along with their usual anti-colitis medication(s) had an increased rate of remission. The data on which this recommendation was made was graded as of moderate quality.
These findings suggest that SMCT1 protein contributes to the suppression of colitis in mice particularly when intestinal levels of SC-FSs are low
and may contribute to producing remissions in the two cited forms of human colitis. However, the studies also suggest that, unlike the findings in mice, SMCT1-bearing intestinal cells in humans do not appear able to produce remissions in these diseases when their intestinal levels of the SC-FAs are low.
Cancers
Colon cancer: In 2003, Li ''et al''
reported that SMCT1 mRNA was present in human normal colon tissue but absent in 38 of 64 (59%) human colon cancer tissues as well as in 23 of 31 (74.1%)
cultured colon cancer
cell lines
An immortalised cell line is a population of cells from a multicellular organism that would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...
. (The study did not assay SMCT1 protein levels.) The loss of SMCT1 mRNA expression in human colon cancer tissues and selected cell lines was closely associated with
hypermethylation
Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms ...
of the
CpG site
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
s in
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
1 of the SMCT1 gene; this location contains the putative area that initiates this gene's
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, often th ...
to form SMCT1 mRNA and protein.
(CpG sites are regions of
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
where a
cytosine
Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
nucleotide
Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
(i.e., "C") followed by a
guanine
Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...
nucleotide (i.e., "G") is repeated in a linear
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is cal ...
of
bases along the DNA's
5' → 3' direction.) This hypermethylation was conducted by an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
,
DNA (cytosine-5)-methyltransferase 1 (i.e., DNM1).
DNM1
methylates cytosines to form
5-methylcytosine
5-Methylcytosine (5mC) is a methylation, methylated form of the DNA base cytosine (C) that regulates gene Transcription (genetics), transcription and takes several other biological roles. When cytosine is methylated, the DNA maintains the same s ...
s in CpG sites that regulate the
expression of nearby genes. Such hypermethylations, when occurring in
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
s, commonly inhibit their expression thereby promoting the cancers that otherwise would be suppressed by these genes.
This study suggested that the ''SLC5A8'' gene directs the formation of the SMCT1 protein which acts to inhibit the development of colon cancer and therefore that the ''SLC5A8'' gene is a tumor suppressor gene.
In a study of 113 patients diagnosed with
Dukes classification stage C (i.e., locally advanced lymph node-positive but no distant
metastases
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
) colon cancer, survival times were significantly longer in patients with tumors that expressed higher levels of SMCT protein (presumed to be SMCT1 protein).
The study concluded that the SMCT1 protein suppresses the development of colon cancer in humans
and slows the progression of human colon cancers that had not spread to distant tissues.
However, another study reported that: 1) ''Slc5a8'' gene knockout mice did not develop colon cancer during a 20 month observation period and 2) there were no differences in the number of tumors formed between ''Slc5a8'' gene knockout and control mice in three models of colon cancer formation, i.e., mice treated with a colon cancer-causing agent, either
azoxymethane
Azoxymethane (AOM) is a carcinogenic and neurotoxic chemical compound used in biological research. It is the oxide of azomethane and is particularly effective for the induction of a colon carcinoma
Carcinoma is a malignancy that develops fro ...
or dextran sulfate, or mice genetically predisposed to develop cancer due to a mutation in their
Adenomatous polyposis coli
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the ''APC'' gene. The APC protein is a Down-regulation, negative regulator that controls beta-catenin concentrations and i ...
gene, i.e., ''Apc
mim'' mice. Thus, the complete absence of SMCT1 protein did not increase the susceptibility of mice to colon cancers that developed "spontaneously" or in three models of colon cancer and thereby question the ''Slc5a8'' gene's role in the development of colon cancer in mice. The study did allow that the mice in these cancer models may have had other SC-FA transporters besides SMCT1 that suppressed the development of the colon cancers. Further studies are needed to resolve these issues.
Breast cancer: The levels of SMCT1 mRNA were reduced in 27 of 30 human breast cancer tumors compared to their levels in adjacent normal breast tissues. This reduction occurred in estrogen receptor positive, estrogen receptor negative, and
triple negative breast cancer
Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...
s. Similarly, cultured
MCF7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers ...
,
T47D, and ZR75.1 human breast cancer cells expressed far lower levels of SMCT1 mRNA than human non-cancerous cultured breast epithelium HMEC cells, breast epithelium HBL100 cells, and (male)
foreskin
In male Human body, human anatomy, the foreskin, also known as the prepuce (), is the double-layered fold of Human skin, skin, Mucous membrane, mucosal and Muscle tissue, muscular tissue at the distal end of the human penis that covers the glans ...
MCF10A cells. When MCF7 cells were forced to express SMCT1 by being transfected with
cDNA
In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...
encoding SMCT1, they developed
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
(i.e., they died by engaging a
cell death program); this development depended on these cells' uptake of extracellular SC-FAs, i.e., pyruvate or propionate. (SMCT1 protein was not measured in this study.) The study concluded that SMCT1 protein acts to suppress the cited types of human breast cancers.
A study of human breast MCF10A cells and the
oncogenic
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
cell lines derived from this cell line, i.e., non-cancerous normal MCF10A1, premalignant MCF10AT1k.cl2, ductal carcinoma in situ MCF10CA1h, and invasive MCF10CA1a.cl1 breast cancer cells concluded that inactivation of the ''SLC5A8'' gene was an early and necessary event in the progression of the non-cancerous cells to invasive cancer cells. The study supported the suggestion that the ''SLC585'' gene is a tumor suppressor gene.
Cervical cancer: A study of 58 patients with
cancer of the cervix
Cervical cancer is a cancer arising from the cervix or in any layer of the wall of the cervix. It is due to the abnormal growth of cells that can invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later sympt ...
found that the average level of SMCT1 mRNA was significantly lower in their cancerous than adjacent, noncancerous cervical tissue. SMCT1 mRNA levels were also lower in three human cervical cancer cell lines (i.e.,
HeLa
HeLa () is an immortalized cell line used in scientific research. It is the oldest human cell line and one of the most commonly used. HeLa cells are durable and prolific, allowing for extensive applications in scientific study. The line is ...
, abd, and CaSki cells) and a human
uterus
The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
cancer cell line (i.e., SiHa cells) than normal human cervical epithelial cells. The proliferation of cultured SiHa cells transfected with a ''SLC5A8'' gene-expressing
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria and ...
was significantly lower than that of SiHA cells transfected with a negative control plasmid. The lower proliferation rate of SiHa cells transfected with the ''SCL5A8'' gene-expressing plasmid was associated with the development of apoptosis in the cancer cells. (SMCT1 protein was not measured in this study.) The study concluded that the SMCT1 protein acts to suppress human cervical cancer at least in part by increasing their cancer cells' rate of apoptosis.
Pancreatic cancer: The
pancreatic
The pancreas (plural pancreases, or pancreata) is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...
cancers of 10 humans expressed low levels or did not express SMCT1 mRNA whereas 11 of 28 adjacent non-cancerous pancreas tissues from these humans expressed relatively high levels of SMCT1 mRNA. The human pancreatic cancer cell lines
PANC-1,
MIA PaCa-2, and Capan2 did not express SMCT1 mRNA and evidenced high hypermethylation levels in the CpG sites of their ''SLC5A8'' gene similar to that in colon cancer. Treatment of these three cell lines with an inhibitor of CpG site methylation, 5-aza-2′-deoxycytidine (also termed
decitabine
Decitabine (i.e., 5-aza-2′-deoxycytidine), sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood ...
), increased their levels of SMCT1 mRNA. (This study did not measure SMCT1 protein.) The study concluded that SMCT1 protein acts to suppress the development and/or progression of human pancreatic cancers.
Lung cancer: SMCT1 mRNA levels were reduced or absent in 9 of 23 (39.1%) human lung cancer tissues compared to their adjacent normal lung tissues. This difference was associated with increased levels of hypermethylation in the CpG sites of the lung cancer tissues similar to that seen in colon cancer. SMCT1 mRNA was also not expressed in 21 of 22 lung cancer cell lines. Analysis of cells in the human
A549 cell
A549 cells are adenocarcinoma, adenocarcinomic human Pulmonary alveolus, alveolar basal lamina, basal epithelial cell (biology), cells, and constitute a cell line that was first developed in 1972 by D. J. Giard, et al. through the removal and cel ...
lung cancer cell line showed that they too had increased levels of hypermethylation in the CpG sites similar to that seen in colon cancer. This cell line was the only one tested for this relationship. (SMCT1 protein levels were not assayed in these studies).
Another study found that patients with
adenocarcinomas of the lung stages I or II (i.e., cancers localized to a small or larger, respectively, part of the lung) who exhibited high methylation levels in the CpG sites of their ''SLC5A8'' gene had shorter
disease-free survival
Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...
times than patients who did not have this methylation pattern. (The study did not measure SMCT1 mRNA or protein levels.)
The two studies respectively concluded that SMCT1 protein inhibits the development and/or progression of the cited human lung cancers
and prolongs the survival of individuals with earlier stages lung adenocarcinomas.
Brain cancer: The following findings were reported in a study of brain cancers. 1) SMCT1 mRNA levels were significantly lower in 13 human
glioma
A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of ...
s than their levels in normal human brain tissues. 2) The human glioma LN229 and LN443 cell lines expressed little or no SMCT1 mRNA, had CpG site hypermethylations similar to that in colon cancer, increased their expression of SMCT1 mRNA when treated with the inhibitor of CpG site methylation, 5-aza-2′-deoxycytidine, and after
transfection
Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to des ...
with a ''SLC5A8'' gene-containing retrovirus vector formed far fewer colonies than LN229 and LN443 cells transfected with an empty viral vector as judged in a laboratory assay that measured the ability of single cells to grow into colonies. And 3) 17 Human grade II
astrocytoma
Astrocytoma is a type of brain tumor. Astrocytomas (also astrocytomata) originate from a specific kind of star-shaped glial cell in the cerebrum called an astrocyte. This type of tumor does not usually spread outside the brain and spinal cord, an ...
s, 10 grade II
oligodendroglioma
Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a oligodendrocyte progenitor cell, glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central ne ...
s, and 13 grade III oligodendrogliomas as well as 9 of 10 mouse oligodendrogliomas had CpG site hypermethylations similar to that seen in colon cancer. Cancers graded as 1, II, III, and 1V are respectively well-
differentiated-low grade, moderately differentiated-intermediate grade, poorly differentiated-high grade, and undifferentiated-high grade cancers. (SMCT1 protein was not assayed in these studies.) The study concluded that SMCT1 protein acts to inhibit the development and/or progression of the cited human brain cancers and may do so at least in part by inhibiting the proliferation of their cancer cells.
Thyroid cancer: SMCT1 mRNA levels in the cancerous tissues of 18 patients with the classical form of
papillary thyroid carcinoma
Papillary thyroid cancer (papillary thyroid carcinoma,
PTC) is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases.Chapter 20 in: 8th edition. It occurs more frequently in women and presents ...
were 40-fold lower than in their
thyroid glands normal tissues. (The classical form of papillary thyroid carcinoma contains true
papillae, i.e., papillae with a central vascular core and epithelial cells that have an enlarged
nuclei with
nuclear membrane
The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer polar membrane, membranes that in eukaryotic cells surround the Cell nucleus, nucleus, which encloses the genome, genetic material.
The nuclear envelope con ...
irregularities and a distinct
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
pattern.) In 90% of these classical carcinomas, CpG site hypermethylations in these cancer cells were similar to that in colon cancer. (The study did not measure SMCT1 protein levels.)
In another study of patients with thyroid disease, SMCT1 mRNA levels in papillary thyroid carcinoma tissues were significantly lower than those in non-cancerous
multinodular goiter
A goitre (British English), or goiter (American English), is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly.
Worldwide, over 90% of goitre cases are ca ...
thyroid tissues. The ''SLC5A8'' gene in papillary thyroid cancer tissues but not in the multinodular goiter tissues had hypermethylations in CpG sites similar to that in colon cancer. (This study did not measure SMCT1 protein.)
The two studies concluded that SMCT1 protein acts to inhibit the development and/or progression of human papillary thyroid carcinomas.
Head & neck cancers: SMCT1 mRNA levels were decreased in 10 of 13 (77%)
head & neck squamous cell carcinomas
Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in Epithelium#Cell types, squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in ...
compared to the levels in the corresponding non-cancerous head & neck tissues (i.e., tongue,
tonsil
The tonsils ( ) are a set of lymphoid organs facing into the aerodigestive tract, which is known as Waldeyer's tonsillar ring and consists of the adenoid tonsil (or pharyngeal tonsil), two tubal tonsils, two palatine tonsils, and the lingual t ...
,
pharynx
The pharynx (: pharynges) is the part of the throat behind the human mouth, mouth and nasal cavity, and above the esophagus and trachea (the tubes going down to the stomach and the lungs respectively). It is found in vertebrates and invertebrates ...
,
larynx
The larynx (), commonly called the voice box, is an organ (anatomy), organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal ...
, and other sites in the oral cavity). This relationship was associated with increased CpG site hypermethylations in the cancer tissues similar to that in colon cancer. Treatment of 5 head & neck squamous carcinoma cell lines (SCC8, SCC11B, SCC17AS, SCC22B, and SCC25) with the CpG site-demethylating agent, 5-aza-2′-deoxycytidine, increased the levels of SMCT1 mRNA in all but the SCC11B cell line. And, SCCB22 cells, which express low levels of SMCT1 mRNA, formed far more colonies in a colony forming assay than SCCBB2 cells that were made to overexpress SMCT1 by being transfected with ''SLC5A8'' gene-expressing pBAB-pro (plasmid #1764)
viral vector
A viral vector is a modified virus designed to gene delivery, deliver genetic material into cell (biology), cells. This process can be performed inside an organism or in cell culture. Viral vectors have widespread applications in basic research, ...
. (This study did not measure SMCT1 protein levels). The study concluded that SMCT1 protein acts to suppress the development and/or progression of these carcinomas and appears to do so at least in part by suppressing their ability to form colonies.
Gastric cancer: Ten human gastric cancer cell lines MKN7, MKN1, JRST, SNU1, KatoIII, NUGC4, SNU638, SH101, HSC44, and HSC45 cells and two mouse gastric cancer cell lines, MKN28 and MKN74 were examined for hypermethylations of the CpG sites similar to that seen in colon cancer. All of these cell lines except MKN1 human and MKN74 mouse gastric cancer cells showed this hypermethylation pattern. Among 7 cell lines tested, i.e., HSC44, HSC45, MKN28, MKN74, NUGC4, Kato III, and SNU638, only MKN74 cells had detectable levels of mRNA for SMCT1. (The study did not measure SMCT1 protein.) Studies in mice and human gastric cancer tissues are needed to relate these findings to gastric cancer.
Prostate cancer: One study reported that the levels of SMCT1 mRNA were undetectable or reduced in 7 of 10 human prostate cancers compared to their normal prostate tissues. The undetectable or reduced levels of SMCT1 were associated with hypermethylations of CpG sites similar to that in colon cancer. Furthermore, SMCT1 mRNA was not expressed in
PC-3 and
DU-145 human prostate cancer cell lines and treatment of these cells with the CpG site demethylating agent, 5-aza-2′-deoxycytidine, increased the levels of SMCT1 mRNA in both cell lines. (This study did not measure SMCT1 protein levels.) The study concluded that SMCT1 protein acted to suppress the development and/or progression of human prostate cancers.
In contrast to these findings, a later study of sugicial specimens from human prostate glands reported that: 1) SMCT1 protein levels in the prostate cancers of 19 patients were 84% higher than their levels in adjacent
benign prostate hyperplasia
Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, urinary retention, inability t ...
(i.e. BPH) tissues; 2) SMCT1 protein levels in 24 prostate cancer tissues were 50% higher, 42% similar to, and only 8% lower than their adjacent
prostate intraepithelial neoplasia (i.e. PIN) tissues; 3) SMCT1 protein levels in 140 prostate gland cancer tissues were significantly higher than in 24 prostate gland BPH tissues snf 32 prostate gland PIN tissues; 4) the levels of SMCT1 mRNA were lower in surgical specimens of 6 among 10 prostate cancer tissues than in the adjacent non-neoplastic tissues; and 5) the SMCT1 proteins were located predominantly in the
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
of prostate cancer tissues. This study contrasted with the previous study in finding that prostate cancers commonly expressed high levels of SMCT1 protein and that the levels of SMCT1 protein trended opposite to its mRNA levels in the prostate cancer tissues from a small number of patients. The study also reported that SMCT1 protein was located principally in the cytoplasm of prostate cancer tissues and suggested that cytoplasmic SMCT1 protein would seem to be inactive in transporting SC-FAs into cells.
These contrasting findings suggest that further studies are needed to measure SMCT1 protein along with SMCT1 mRNA levels and to identify the
subcellular location (e.g., surface membrane ''versus'' cytoplasm) of SMCT1 proteins in normal, BPH, PIN, and cancer prostate tissue and perhaps also in the normal and cancerous tissues of the other cancers cited here.
See also
Sodium-coupled monocarboxylate transporter 2
Sodium-coupled monocarboxylate transporter 2 (i.e., SMCT2, also termed SLC5A12) is a plasma membrane transport protein in the solute carrier family. It transports sodium cations (i.e., Na+) in association with the anionic forms (see conjugated ba ...
References
{{Solute carrier family, bg, bg0
Solute carrier family