Synergistically suppressive effects on colorectal cancer cells by combination of mTOR inhibitor and glycolysis inhibitor, Oxamate.

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide, representing a major cancer burden. As a natural mTOR inhibitor, rapamycin has been demonstrated to regulate various cellular biological behaviors of cancer cells, including growth inhibition and induction of apoptosis in multiple types of malignant tumors. In this study, we report mTOR inhibitor treatments significantly decreased colon cancer cells glucose metabolism. The glucose uptake and lactate product of DLD-1 and LoVo cells were suppressed by rapamycin. In addition, rapamycin resistant DLD-1 cells display elevated glycolysis rate. The expressions of glycolysis enzymes, Hexokinase 2, PKM2 and LDHA are upregulated in rapamycin resistant cells. We observed promotion of cellular glycolysis by overexpressing LDHA renders colon cancer cells resistant to rapamycin and inhibition of glycolysis by knockdown LDHA sensitizes colon cancer cells to rapamycin. Importantly, we demonstrate the combination of rapamycin and glycolysis inhibitor, Oxamate showed a synergistically inhibitory effect on colon cancer cells. Our study will contribute to the development of therapeutic approaches through combination of mTOR inhibitor with glycolysis inhibitor for the treatment of colorectal cancer patients.