Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

See all formats and pricing
More options …
Ahead of print


MCT1, MCT4 and CD147 expression and 3-bromopyruvate toxicity in colorectal cancer cells are modulated by the extracellular conditions

Joana Pereira-Vieira
  • Center of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal
  • CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra, 1317, 4585-116, Gandra, PRD, Portugal
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ João Azevedo-SilvaORCID iD: https://orcid.org/0000-0003-1754-9254 / Ana Preto
  • Center of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Margarida Casal
  • Center of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Odília Queirós
  • Corresponding author
  • CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra, 1317, 4585-116, Gandra, PRD, Portugal
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2019-02-14 | DOI: https://doi.org/10.1515/hsz-2018-0411


Monocarboxylate transporters (MCTs) inhibition leads to disruption in glycolysis, induces cell death and decreases cell invasion, revealing the importance of MCT activity in intracellular pH homeostasis and tumor aggressiveness. 3-Bromopyruvate (3BP) is an anti-tumor agent, whose uptake occurs via MCTs. It was the aim of this work to unravel the importance of extracellular conditions on the regulation of MCTs and in 3BP activity. HCT-15 was found to be the most sensitive cell line, and also the one that presented the highest basal expression of both MCT1 and of its chaperone CD147. Glucose starvation and hypoxia induced an increased resistance to 3BP in HCT-15 cells, in contrast to what happens with an extracellular acidic pH, where no alterations in 3BP cytotoxicity was observed. However, no association with MCT1, MCT4 and CD147 expression was observed, except for glucose starvation, where a decrease in CD147 (but not of MCT1 and MCT4) was detected. These results show that 3BP cytotoxicity might include other factors beyond MCTs. Nevertheless, treatment with short-chain fatty acids (SCFAs) increased the expression of MCT4 and CD147 as well as the sensitivity of HCT-15 cells to 3BP. The overall results suggest that MCTs influence the 3BP effect, although they are not the only players in its mechanism of action.

This article offers supplementary material which is provided at the end of the article.

Keywords: 3-bromopyruvate; colorectal cancer; monocarboxylate transporters; Warburg effect


  • Al Okail, M.S. (2010). Cobalt chloride, a chemical inducer of hypoxia-inducible factor-1α in U251 human glioblastoma cell line. J. Saudi Chem. Soc. 14, 197–201.CrossrefGoogle Scholar

  • Azevedo-Silva, J., Queirós, O., Ribeiro, A., Baltazar, F., Young, K.H., Pedersen, P.L., Preto, A., and Casal, M. (2015). The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH. Biochem. J. 467, 247–258.CrossrefPubMedGoogle Scholar

  • Azevedo-Silva, J., Queirós, O., Baltazar, F., Ułaszewski, S., Goffeau, A., Ko, Y.H., Pedersen, P.L., Preto, A., and Casal, M. (2016). The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside. J. Bioenerg. Biomembr. 48, 349–362.CrossrefPubMedGoogle Scholar

  • Bao, W., Chen, M., Zhao, X., Kumar, R., Spinnler, C., Thullberg, M., Issaeva, N., Selivanova, G., and Stromblad, S. (2011). PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo. Cell Cycle 10, 301–307.PubMedCrossrefGoogle Scholar

  • Berg, K.C.G., Eide, P.W., Eilertsen, I.A., Johannessen, B., Bruun, J., Danielsen, S.A., Bjornslett, M., Meza-Zepeda, A., Eknaes, M., Lind, G.E., et al. (2017). Multi-omics of 34 colorectal cancer cell lines – a resource for biomedical studies. Mol. Cancer 116, 1–16.Google Scholar

  • Bhardwaj, V., Rizvi, N., Lai, M.B., Lai, J.C.K., and Bhushan, A. (2010). Glycolytic enzyme inhibitors affect pancreatic cancer survival by modulating its signaling and energetics. Anticancer Res. 30, 743–749.PubMedGoogle Scholar

  • Birsoy, K., Wang, T., Possemato, R., Yilmaz, O.H., Kock, C.E., Chen, W., Hutchins, A.W., Gultekin, Y., Peterson, T.R., Carette, J.E.C., et al. (2013). MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat. Genet. 45, 104–108.CrossrefPubMedGoogle Scholar

  • Borthakur, A., Saksena, S., Gill, R.K., Alrefaii, A., Ramaswamy, K., and Dudeja, P.K. (2008). Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: involvement of NF-κB pathway. J. Cell Biochem. 103, 1452–1463.PubMedCrossrefGoogle Scholar

  • Canani, R.B., Costanzo, M.D., Leone, L., Pedata, M., Meli, R., and Calignano, A. (2011). Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J. Gastroenterol. 17, 1519–1528.PubMedCrossrefGoogle Scholar

  • Damaghi, M., Wojtkowiak, J.W., and Gillies, R.J. (2013). pH sensing and regulation in cancer. Front. Physiol. 4, 1–10.Google Scholar

  • DeBerardinis, R.J. and Chandel, N.S. (2016). Fundamentals of cancer metabolism. Sci. Adv. 2, 1–18.Google Scholar

  • Donohoe, D.R., Collins, L.B., Wali, A., Bigler, R., Sun, W., and Bultman, S.J. (2012). The Warburg effect dictates the mechanism of butyrate mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626.PubMedCrossrefGoogle Scholar

  • Donohoe, D.R., Holley, D., Collins, L.B., Montgomery, S.A., Whitmore, A.C., Hillhouse, A., Curry, K.P., Renner, S.W., Greenwalt, A., Ryan, E.P., et al. (2014). A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 4, 1387–1397.CrossrefGoogle Scholar

  • Enerson, B.E. and Drewes, L.R. (2003). Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery. J. Pharm. Sci. 92, 1531–1544.CrossrefPubMedGoogle Scholar

  • Fang, J., Quinones, Q.J., Holman, T.L., Morowitz, M.J., Wang, Q., Zhao, H., Sivo, F., Maris, J.M., and Wahl, M.L. (2006). The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol. Pharmacol. 70, 2108–2115.PubMedCrossrefGoogle Scholar

  • Fantin, V.R., St-Pierre, J., and Leder, P. (2006). Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434.PubMedCrossrefGoogle Scholar

  • Ferro, S., Azevedo-Silva, J., Casal, M., Côrte-Real, M., Baltazar, F., and Preto, A. (2016). Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications. Oncotarget 1, 1–15.Google Scholar

  • Gallagher, S.M., Castorino, J.J., Wang, D., and Philp, N.J. (2007). Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 67, 4182–4189.CrossrefPubMedGoogle Scholar

  • Ganapathy-kanniappan, S. and Geschwing, J-F.H. (2013). Tumor glycolysis as a target for cancer therapy. BioMed. Cent. 12, 1–11.Google Scholar

  • Gatenby, R.A. and Gillies, R.J. (2004). Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899.CrossrefPubMedGoogle Scholar

  • Grass, G.D. and Toole, B.P. (2016). How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity. Biosci. Rep. 36, 1–16.Google Scholar

  • Greaves, M. and Maley, C.C. (2012). Clonal evolution in cancer. Nature 481, 306–313.CrossrefPubMedGoogle Scholar

  • Hadjiagapiou, C., Schmidt, L., Dudeja, P.K., Layden, T.J., and Ramaswamy, K. (2000). Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1. Am. J. Physiol. Gastrointest. Liver Physiol. 279, 775–780.CrossrefGoogle Scholar

  • Halestrap, A.P. (2012). The monocarboxylate transporter family-structure and functional characterization. IUBMB Life 64, 1–9.PubMedCrossrefGoogle Scholar

  • Halestrap, A.P. and Meredith, D. (2004). The SLC16 gene family – From monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflüger’s Arch. Eur. J. Physiol. 447, 619–628.CrossrefGoogle Scholar

  • Halestrap, A.P. and Wilson, M.C. (2012). The monocarboxylate transporter family-role and regulation. IUBMB Life 64, 109–119.PubMedCrossrefGoogle Scholar

  • Hanahan, D. and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674.CrossrefPubMedGoogle Scholar

  • Ho, N., Morrison, J., Silva, A., and Coomber, B.L. (2016). The effect of 3-bromopyruvate on human colorectal cancer cells is dependent on glucose concentration but not hexokinase II expression. Biosci. Rep. 36, 1–13.Google Scholar

  • Ippolito, J.E., Brandenburg, M.W., Ge, X., Crowley, J.R., Kirmess, K.M., Som, A., D’Avignon, D.A., Arbeit, J.M., Achilefu, S., Yarasheski, K.E., et al. (2016). Extracellular pH modulates neuroendocrine prostate cancer cell metabolism and susceptibility to the mitochondrial inhibitor niclosamide. PLoS One 11, 1–26.Google Scholar

  • Jan, G., Belzacq, A.S., Haouzi, D., Rouault, A., Métivier, D., Kroemer, G., and Brenner, C. (2002). Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria. Cell Death Differ. 9, 179–188.PubMedCrossrefGoogle Scholar

  • Kato, Y., Ozawa, S., Miyamoto, C., Maehata, Y., Suzuki, A., Maeda, T., and Baba, Y. (2013). Acidic extracellular microenvironment and cancer. Cancer Cell Int. 13, 1–8.Google Scholar

  • Ke, X., Fei, F., Chen, Y., Xu, L., Zhang, Z., Huang, Q., Zhang, H., Yang, H., Chen, Z., and Xing, J. (2012). Hypoxia upregulates CD147 through a combined effect of HIF-1α and Sp1 to promote glycolysis and tumor progression in epithelial solid tumors. Carcinogenesis 33, 1598–1607.CrossrefPubMedGoogle Scholar

  • Keku, T.O., Dulal, S., Deveaux, A., Jovov, B., and Han, X. (2015). The gastrointestinal microbiota and colorectal cancer. Am. J. Physiol. 308, 351–363.Google Scholar

  • Kennedy, K.M. and Dewhirst, M.W. (2010). Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol. 6, 1–32.Google Scholar

  • Kirk, P., Wilson, M.C., Heddle, C., Brown, M.H., Barclay, A.N., and Halestrap, A.P. (2000). CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J. 19, 3896–3904.PubMedCrossrefGoogle Scholar

  • Ko, Y.H., Pedersen, P.L., and Geschwind, J.F. (2001). Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett. 173, 83–91.PubMedCrossrefGoogle Scholar

  • Kong, L.M., Liao, C.G., Fei, F., Guo, X., Xing, J.L., and Chen, Z.N. (2010). Transcription factor Sp1 regulates expression of cancer-associated molecule CD147 in human lung cancer. Cancer Sci. 101, 1463–1470.CrossrefPubMedGoogle Scholar

  • Kroemer, G. and Pouyssegur, J. (2008). Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13, 472–82.CrossrefPubMedGoogle Scholar

  • Liu, T., Li, J., Liu, Y., Xiao, N., Suo, H., Xie, K., Yang, C., and Wu, C. (2012). Short-Chain fatty acids suppress lipopolysaccharide-Induced production of nitric oxide and proinflammatory cytokines through inhibition of NF-κB Pathway in RAW264.7 cells. Inflammation 35, 1676–1684.CrossrefPubMedGoogle Scholar

  • Marques, C., Oliveira, C.S.F., Alves, S., Chaves, S.R., Coutinho, O.P., Côrte-Real, M., and Preto, A. (2013). Acetate-induced apoptosis in colorectal carcinoma cells involves lysosomal membrane permeabilization and cathepsin D release. Cell Death Dis. 4, 1–11.Google Scholar

  • Miranda-Gonçalves, V., Baltazar, F., and Reis, R.M. (2015). Brain tumor metabolism – unraveling its role in finding new therapeutic targets. In: Molecular Considerations and Evolving Surgical Management Issues in the Treatment of Patients with a Brain Tumor, Chapter 4, T. Lichtor, eds. (London, UK: IntechOpen), pp. 83–102.Google Scholar

  • Morris, M.E. and Felmlee, M.A. (2008). Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse γ-hydroxybutyric acid. AAPS J. 10, 311–321.CrossrefPubMedGoogle Scholar

  • Nakai, M., Chen, L., and Nowak, R.A. (2006). Tissue distribution of basigin and monocarboxylate transporter 1 in the adult male mouse: a study using the wild type and basigin gene knockout mice. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 40, 1301–1315.Google Scholar

  • Nakajima, E.C. and Van Houten, B. (2013). Metabolic symbiosis in cancer: refocusing the Warburg lens. Mol. Carcinog. 52, 329–337.PubMedCrossrefGoogle Scholar

  • Nelson, D.L. and Cox, M.M. (2004). Lehninger Principles of Biochemistry, 4th Ed. Chapter 14 (New York: W. H. Freeman), pp. 523–525.Google Scholar

  • Ngo, D.C., Ververis, K., Tortorella, S.M., and Karagiannis, T.C. (2015). Introduction to the molecular basis of cancer metabolism and the Warburg effect. Mol. Biol. Rep. 42, 819–823.CrossrefPubMedGoogle Scholar

  • Oliveira, C.S.F., Pereira, H., Alves, S., Castro, L., Baltazar, F., Chaves, S.R., Preto, A., and Côrte-Real, M. (2015). Cathepsin D protects colorectal cancer cells from acetate-induced apoptosis through autophagy independent degradation of damaged mitochondria. Cell Death Dis. 6, 1–11.Google Scholar

  • Orue, A., Chavez, V., Strasberg-Rieber, M., and Rieber, M. (2016). Hypoxic resistance of KRAS mutant tumor cells to 3-Bromopyruvate is counteracted by Prima-1 and reversed by N-acetylcysteine. BMC Cancer 16, 1–16.Google Scholar

  • Parks, S.K., Cormerais, Y., Marchiq, I., and Pouyssegur, J. (2016). Hypoxia optimises tumour growth by controlling nutrient import and acidic metabolite export. Mol. Aspects Med. 47–48, 3–14.PubMedGoogle Scholar

  • Pérez-Escuredo, J., Hée, V.F., Sboarina, M., Falces, J., Payen, V.L., Pellerin, L., and Sonveaux, P. (2016). Monocarboxylate transporters in the brain and in cancer. Biochim. Biophys. Acta 1863, 2481–2497.CrossrefPubMedGoogle Scholar

  • Pinheiro, C., Longatto-Filho, A., Azevedo-Silva, J., Casal, M., Schmitt, F.C., and Baltazar, F. (2012). Role of monocarboxylate transporters in human cancers: state of the art. J. Bioenerg. Biomembr. 44, 127–139.PubMedCrossrefGoogle Scholar

  • Porporato, P.E., Dhup, S., Dadhich, R.K., Copetti, T., and Sonveaux, P. (2011). Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol. 2, 1–18.Google Scholar

  • Queirós, O., Preto, A., Pacheco, A., Pinheiro, C., Azevedo-Silva, J., Moreira, R., Pedro, M., Ko, Y.H., Pederson, P.L., Baltazar, F., et al. (2012). Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate. J Bioenerg Biomembr. 44, 141–153.PubMedCrossrefGoogle Scholar

  • Seyfried, T.N. and Shelton, L.M. (2010). Cancer as a metabolic disease. Nutrit. Metab. 7, 1–22.Google Scholar

  • Shanware, N.P., Mullen, A.R., DeBerardinis, R.J., and Abraham, R.T. (2011). Glutamine: pleiotropic roles in tumor growth and stress resistance. J. Mol. Med. 89, 229–236.CrossrefPubMedGoogle Scholar

  • Son, J., Lyssiotis, C.A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R.M., Ferrone, C.R., Mullarky, E., Shuh-Chang, N., et al. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105.PubMedCrossrefGoogle Scholar

  • Sonveaux, P., Végran, F., Schroeder, T., Wergin, M.C., Verrax, J., Rabbani, Z.N., DeSaedeleer, C.J., Kennedy, K.M., Diepart, C., Jordan, B.F., et al. (2008). Targeting lactate-fueled respiration selectivelt kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 1–13.Google Scholar

  • Swietach, P., Vaughan-Jones, R.D., and Harris, A.L. (2007). Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis. Rev. 26, 299–310.CrossrefPubMedGoogle Scholar

  • Trainer, D.L., Kline, T., McCabe, F.L., Faucette, L.F., Field, J., Chaikin, M., Anzano, M., Rieman, D., Hoffstein, S., Li, D-J., et al. (1988). Biological characterization and oncogene expression in human colorectal carcinoma cell lines. Int. J. Cancer 41, 287–296.CrossrefPubMedGoogle Scholar

  • Ullah, M.S., Davies, A.J., and Halestrap, A.P. (2006). The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J. Biol. Chem. 281, 9030–9037.PubMedCrossrefGoogle Scholar

  • Vander Heiden, M., Cantley, L., and Thompson, C. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033.PubMedCrossrefGoogle Scholar

  • Walters, D.K., Arendt, B.K., and Jelinek, D.F. (2013). CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells. Cell Cycle 12, 3175–3183.PubMedGoogle Scholar

  • Warburg, O. (1956). On the origin of cancer cells on the origin of cancer. Science 123, 309–14.PubMedCrossrefGoogle Scholar

  • Xia, Y., Choi, H.K., and Lee, K. (2012). Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur. J. Med. Chem. 49, 24–40.CrossrefPubMedGoogle Scholar

  • Xu, R.H., Pelicano, H., Zhou, Y., Carew, J.S., Feng, L., Bhalla, K.N., Keating, M.J., and Huang, P. (2005). Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 65, 613–621.PubMedGoogle Scholar

  • Yuan, Y., Hilliard, G., Ferguson, T., and Millhorn, D.E. (2003). Cobalt inhibits the interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-α. J. Biol. Chem. 278, 15911–15916.CrossrefPubMedGoogle Scholar

  • Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Wilson, J.K.V., Markowitz, S., Zhou, S., et al. (2009). Pathway mutations in tumor cells. Science 325, 1555–1559.PubMedCrossrefGoogle Scholar

About the article

Received: 2018-10-26

Accepted: 2019-01-16

Published Online: 2019-02-14

Conflict of interest statement: The authors declare no conflict of interest.

Citation Information: Biological Chemistry, 20180411, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0411.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Supplementary Article Materials

Comments (0)

Please log in or register to comment.
Log in