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Introduction to Regulation of Monocarboxylate Transporter

The gut microbiota consists of the combined genome of the intestine-inhabiting organisms including bacteria, archaea, viruses and fungi. The human intestine holds trillions of bacteria that make up more genetic material than most of the body's human cells. The dispersion of intestinal microbiota is spatial, with the colon involving the greatest microorganism abundance and diversity (Thursby & Juge, 2017). Cancer is a disease which depends on many factors, and is the second-largest reason for death in the world. In recent times, multiple studies have demonstrated a double role the gut microflora plays in taking care of health of host. Good microflora may produce a variety of bioproducts and metabolites essential to support the host and homeostasis of the gut. In comparison, many bacteria populations that grow during produce increased rates of toxins that can actually cause both inflammatory response and tumor progression (Vivarelli et al., 2019). Relevantly, intestinal microbiota may communicate with both the host and directly modulate the immune cells and the gut epithelium. Tumorigenesis was among the most studied of all gut microbiome associated pathologies (Bhutia et al., 2017).

Both local gastro - intestinal cancers and other distal tumors have been found to be related. Metabolomics and metagenomics studies have demonstrated the gastrointestinal microbiome's dual role in cancer prevention, tumorigenesis and anti-cancer therapies. The gut microbiome may in reality be either tumor-suppressive or oncogenic. While this relation has been studied since a long time ago, it is characterized only partially (Bultman et al., 2016). All present understanding, in addition, emphasizes the complexity and bidirectionality of the existing link between microbiome and cancer. As a result, the development of cancer may alter the microbiome, and changes in microbiome can, in effect, influence the progression of cancer.

Literature Review of Regulation of Monocarboxylate Transporter

Bacterial fermentation of the dietary fiber produces short-chain fatty acids (SCFA; propionate, butyrate and acetate) in the colon. While protonated diffusion is an essential route, carrier-dependent processes constitute the main route for SCFA 's entrance into colonic epithelium in its anionic form. Lactate cancer exchanges are regulated by SLC16 gene family monocarboxylate transporters (MCTs), which actively transmit lactate and protons across the cell membrane (McCullagh et al., 1996). Several transport systems function in SCFA's cellular uptake. The MCT1 has been found to be getting expressed in the skeletal and heart muscles as well.( Bonen et al., 2012)( Dubouchaud et al., 2000).

 The primary isoforms of the MCT expressed by cancer cells are MCT1 and the MCT4. The expression of these transport proteins is greatly altered in colon cancer and ulcerative colitis (Curry et al., 2013). The tumor-associated changes take place through p53 and HIF1α transcription factors, and through methylation promoters. Because SCFA is essential for optimum colonic safety, the carriers essential for the introduction and transcellular transmission of the bacterial products into the colonic epithelium is significant indicators of colonic function under normal physiological circumstances and in diseases and disorders (Sivaprakasam et al., 2017).

MCT1 and MCT4 (SLC16A1 and SLC16A3 respectively) are SCFA electroneutral H+-coupled controlled transport. The MCT1 is present in the colon basolateral lining and the apical membrane of the colonic epithelium while MCT4 is present only in the basolateral membrane. In the apical membrane the anion-exchange mechanism takes place, Whereas the anionic SCFA entry into the cell is combined with bicarbonate efflux (Hong et al., 2014); the molecular mechanism of this exchange is still unclear. These all protein transporters are heavily regulated, especially through their own substrates; this process includes cell-surface receptor with SCFA as chemical messengers. Expression of such transporters is significantly altered in colon cancer and ulcerative colitis.

Extracellular acidosis arising from rapid metabolism in tumors facilitates movement, invasion , and metastasis of cancer cells. While the normal cells undergo apoptosis at lower extracellular pH, cancerous cells are immune because the cancer cells possess various transportation enzymes and proteins to control the intracellular pH of the cell. In addition, a acidic pH triggers proteolytic enzymes that redefine making changes in the extracellular matrix to facilitate the migration and proliferation of the cancer cells. A passive lactic acid transporter, monocarboxylate transporter MCT1 has drawn attention as a method for small drug molecules to prevent development of tumours. In the present article, we cite evidence of a the role of MCT1 in cancer cell movement which goes far beyond function as a transporter of lactic acids.

The MCT1 activates the transcription factor NF-ÿB to facilitate the metastatis of cancer cells independently of the activity of MCT1 transporters. Although the pharmacological inhibition of MCT1 did not modulate migration of cancer cells centered on MCT1, in vivo suppression or genetic elimination of MCT1 prevented movement, infiltration, and random metastasis. The results increase the risk that the metastatic spread of cancer cells may not be effectively prevented by pharmacological inhibitors of MCT1-mediated lactic acid transport. However, MCT1 can function bidirectionally as a passive transporter and has even been identified to promote export of lactic acid from cancerous cells. Yes, the directionality of the transportation of MCT1-driven SCFA like lactic acid relies on the lactate gradient and the protons present across the membranes.

The tumor-associated changes take place through p53 and HIF1α transcriptional regulation, and through methylation promoters. Since SCFA is necessary for colon safety, the carriers accountable for the moving inside and transcellular transmission of the bacterial products into epithelium of the colon are important aspects of colonic function within physiological environment and in diseases and conditions (Sonveaux et al., 2012). Another principal fuel for colonocytes is Butyrate which is also a SCFA and is produced by the bacterial fermentation of the colon's undigested carbohydrates. In a research studies, the role of the apically localized isoform 1 (MCT1) monocarboxylate transporter also transport of butyrate like the lactic acid into Caco-2 cells which is a colon cell lines form humans. Many other researchers have cloned the gene promoter region of the MCT, in an attempt to study gene regulation, and identified cis components for key transcriptional regulators in MCT1. A previous study documented butyrate production in human epithelial cells and also showed up-regulation of the protein MCT1 expression, but it does not understand the specific mechanisms of this expression. In another studies butyrate, a substratum for MCT1, is used and shown to stimulates MCT1 promoters production in Caco-2 cells. The impact was dose-dependent and butyrate-specific, as was ineffective with other prevalent , acetate, propionate and SCFAs (Borthakur et al., 2008).

MCT1 is a member of proton-linked monocarboxylate transporters (MCTs) family, believed to contain at least 14 mammalian isoforms. Of these were characterized structurally and functionally well by four isoforms (MCT1-MCT4). A group have already reported the existence of specific MCT isoforms throughout the of the human intestinal epithelium. Proton-linked transportation of SCFA such as pyruvate and lactate, and ketone bodies has been shown to be catalyzed by the MCTs. Propionate , butyrate and acetate, are the main SCFAs formed in the gut during the bacterial fermentation of dietary fibre (Murray et al., 2005).

Research studies have shown that fast expanding glycolytic tumors involve metabolism of energy and intra - cellular pH in close connection with CD147 / BASIGIN glycoprotein (BSG) by the activity of two main transporters proteins, MCT1 and hypoxia-inducible transporter MCT4. In addition to investigating and verifying the exporting obstruction of lactic acid as an antitumor strategy, the researcher have disrupted the genes of MCT4 and BSG in the colon cancer cells line of hunam (LS174 T) and glioblastoma (U87) cell lines via zinc finger nucleases. Next, the group showed that the loss of MCT4 substantially sensitized cells to AZD3965 which is inhibitor of MCT 1. Next the researchers demonstrated that BSG knockout contributes to a 10-fold and 6-fold decline in lactate translocation in MCT1 and MCT4, collectively. As a result , cells accumulated a reservoir of pyruvic and lactic acids intracellular, exacerbated by the MCT1 blocker, that further reduced pH and glucose breakdown (Marchiq et al., 2015).

Results of Regulation of Monocarboxylate Transporter

Western blotting

 Increased expression of CD147 has been suggested for lactate monocarboxylate transporters (MCTs), to play a critical part in cancer development via CD147 chaperone action. In the immunoblotting assay it was clear that the both the CD147 and the MCT1 is not getting expressed in the colon cancer cell lines RT4, HT-29, T84, and DLD1, but it is getting expressed in human colon cells. The results clearly demonstrate that CD147 interacts beyond MCTs with membrane carriers and displays a defensive function for many of its partners. The results also emphasize on using MCT-1 as a potential therapeutic target for the colon cancer.

References for Regulation of Monocarboxylate Transporter

Bhutia YD, Ogura J, Sivaprakasam S, Ganapathy V. Gut microbiome and colon cancer: Role of bacterial metabolites and their molecular targets in the host. Curr Colorectal Cancer Rep. 2017;13:111–118.

Bonen, A. (2001). The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. European Journal of Applied Physiology86(1), 6-11.

Borthakur, A., Saksena, S., Gill, R. K., Alrefai, W. A., Ramaswamy, K., & Dudeja, P. K. (2008). Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-kappaB pathway. Journal of Cellular Biochemistry103(5), 1452–1463. https://doi.org/10.1002/jcb.21532

Bultman SJ. The microbiome and its potential as a cancer preventive intervention (2016). Semin Oncol. 43:97–106.

Curry, J. M., Tuluc, M., Whitaker-Menezes, D., Ames, J. A., Anantharaman, A., Butera, A., ... & Martinez-Outschoorn, U. E. (2013). Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle12(9), 1371-1384.

Dubouchaud, H., Butterfield, G. E., Wolfel, E. E., Bergman, B. C., & Brooks, G. A. (2000). Endurance training, expression, and physiology of LDH, MCT1, and MCT4 in human skeletal muscle. American Journal of Physiology-Endocrinology And Metabolism278(4), E571-E579.

Hong, C. S., Graham, N. A., Gu, W., Camacho, C. E., Mah, V., Maresh, E. L., ... & Behbahan, I. S. (2016). MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4. Cell Reports14(7), 1590-1601.

Marchiq, I., Le Floch, R., Roux, D., Simon, M. P., & Pouyssegur, J. (2015). Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Research75(1), 171–180. https://doi.org/10.1158/0008-5472.CAN-14-2260

McCullagh, K. J., Poole, R. C., Halestrap, A. P., O'Brien, M., & Bonen, A. (1996). Role of the lactate transporter (MCT1) in skeletal muscles. American Journal of Physiology-Endocrinology And Metabolism271(1), E143-E150.

Murray, C. M., Hutchinson, R., Bantick, J. R., Belfield, G. P., Benjamin, A. D., Brazma, D., ... & Evans, L. R. (2005). Monocarboxylate transporter MCT1 is a target for immunosuppression. Nature Chemical Biology1(7), 371-376.

Sivaprakasam, S., Bhutia, Y. D., Yang, S., & Ganapathy, V. (2017). Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Comprehensive Physiology8(1), 299–314. https://doi.org/10.1002/cphy.c170014

Sonveaux, P., Copetti, T., De Saedeleer, C. J., Végran, F., Verrax, J., Kennedy, K. M., ... & Gallez, B. (2012). Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PloS One7(3), e33418.

Thursby, E., & Juge, N. (2017). Introduction to the human gut microbiota. Biochemical Journal474(11), 1823-1836.

Vivarelli, S., Salemi, R., Candido, S., Falzone, L., Santagati, M., Stefani, S., ... & Libra, M. (2019). Gut microbiota and cancer: from pathogenesis to therapy. Cancers11(1), 38.

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