MCT4 Expression is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Monocarboxylate transporters (MCTs) are transmembrane proteins which control the lactate metabolism and associated with poor prognosis in solid tumors including colorectal cancer (CRC). Here we aimed to investigate the biological and clinical role of MCTs in CRC and to assess the potential of therapeutic application. A total of 16 human CRC cell lines, 11 patient-derived cells from malignant ascites (PDC), and 39 matched pairs of primary CRC 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 immunohistochemistry (IHC) and used for survival analysis. Expression of MCTs was demonstrated in CRC 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 MTC4 was markedly increased in PDCs and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α 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 CRC with peritoneal carcinomatosis and serve as a prognostic indicator.

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