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

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 and 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 and 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-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 colorectal cancer with peritoneal carcinomatosis and serve as a prognostic indicator. .

Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

“…Consistent with the results seen in KRAS‐activated MEF cells, si COUP‐TFII also suppressed LDHA protein expression, p‐S6K (T389) levels, and intracellular lactate levels in KRAS‐activated human cancer cells (Figs B and EV2B and C), implying that the association of COUP‐TFII and mTORC1 activation applies to human KRAS‐activated cancer cells. The expression status of MCT1 and MCT4 in KRAS‐activated cancer cells (Fig EV2D) was similar to those of previous results . Next, we proposed that lactate acts as a signaling molecule, transmitting the effects of COUP‐TFII on mTORC1 activation.…”

Monocarboxylate Transporter 4 (MCT4) Knockout Mice Have Attenuated 4NQO Induced Carcinogenesis; A Role for MCT4 in Driving Oral Squamous Cell Cancer

“…Large in situ lesions were not found in tongues from MCT4 −/− mice treated with 4NQO since these epithelial cells cannot shift their metabolism toward a hyperglycolytic state. It has been shown that inhibition of the lactate transport has a negative effect on cell proliferation (17, 37). The intracellular accumulation of lactate slows the glycolytic flux by directly inhibiting hexokinase and phosphofructokinase (38) and by decreasing the NAD + /NADH ratio.…”

Exploiting Current Understanding of Hypoxia Mediated Tumour Progression for Nanotherapeutic Development

“…In addition, inhibition of MCT-1 significantly reduced lactate production, cell proliferation and invasion [127]. Furthermore, HIF-1α knockdown in the SW48 CRC cell line has also been shown to reduce MCT-4 expression in vitro [128], indicating that MCTs could be potentially acted on as therapeutic targets.…”