MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis

Hee Kyung Kim, In Kyoung Lee, Heejin Bang, Hee Cheol Kim, Woo Yong Lee, Seong Hyeon Yun, Jeeyun Lee, Su Jin Lee, Young Suk Park, Kyoung Mee Kim, Won Ki Kang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Monocarboxylate transporters (MCT) are transmembrane proteins that control the lactate metabolism and are associated with poor prognosis in solid tumors, including colorectal cancer. Here, we aimed to investigate the biological and clinical role of MCTs in colorectal cancer and to assess the potential of therapeutic application. A total of 16 human colorectal cancer cell lines, 11 patient-derived cells from malignant ascites [patient-derived cells (PDC)], and 39 matched pairs of primary colorectal cancer and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo. siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by IHC and used for survival analysis. Expression of MCTs was demonstrated in colorectal cancer cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo. An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MCT4 was markedly increased in PDCs, and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia-inducible factor 1-a (HIF1a) was also highly expressed in PDCs, whereas HIF1a knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for colorectal cancer with peritoneal carcinomatosis and serve as a prognostic indicator.

Original languageEnglish
Pages (from-to)838-848
Number of pages11
JournalMolecular cancer therapeutics
Volume17
Issue number4
DOIs
StatePublished - Apr 2018

Fingerprint Dive into the research topics of 'MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis'. Together they form a unique fingerprint.

  • Cite this

    Kim, H. K., Lee, I. K., Bang, H., Kim, H. C., Lee, W. Y., Yun, S. H., Lee, J., Lee, S. J., Park, Y. S., Kim, K. M., & Kang, W. K. (2018). MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis. Molecular cancer therapeutics, 17(4), 838-848. https://doi.org/10.1158/1535-7163.MCT-17-0535