Pro‐inflammatory Cytokines Increase Glycolysis through Upregulation of Uncoupling Protein and Akt Activation in Colorectal Cancer Cells

Abstract

Non‐cancerous colonocytes use butyrate, which is a short‐chain fatty acid derived from the fermentation of dietary fiber, as a primary energy source. In contrast, cancerous colonocytes use glucose as their preferred energetic substrate and undergo enhanced glycolysis or the Warburg effect. It has been reported that increased production of pro‐inflammatory cytokines such as interleukin1 beta and tumor necrosis factor alpha (TNFalpha) promote glycolysis. Previously, we have shown that interleukin1 beta increased glycolysis and decreased butyrate oxidation. However, the mechanism underlying how this pro‐inflammatory cytokine increased glycolysis was unclear. Here, we have discovered that Uncoupling Protein 2 (UCP2) appears to mediate the elevation in glycolysis induced by interleukin1 beta. UCP2 is a mitochondrial protein that transports the protons back into the mitochondrial matrix, thus dissipating the proton gradient and reducing ATP production. UCP2 is upregulated in various cancers such as breast, prostate, skin, and colorectal cancers. We hypothesize that interleukin1 beta promotes glycolysis by upregulating UCP2 and activating Akt in colorectal cancer cells. We have found colorectal cancer cells treated with interleukin1 beta showed elevated UCP2 expression and increased Akt activation. Next, we utilized the Seahorse XFe24 analyzer to check whether interleukin1 beta affects proton leak and ATP production in colorectal cancer cells. Preliminary data suggests that interleukin1 beta increases proton leak and decreases ATP production in mitochondria, which is consistent with the upregulation of UCP2 and demonstrates a functional consequence. To study whether UCP2 mediates the interleukin1 beta effect toward increasing glycolysis, we created a stable UCP2 knockdown in colorectal cancer cells and tested whether colorectal cancer cells that had diminished UCP2 from the RNAi knockdown did not show an increase in glycolysis when treated with interleukin1 beta as compared to RNAi mock colorectal cancer cells. Our preliminary data allude to a role for UCP2 in mediating the interleukin1 beta induced increase in glycolysis observed in colorectal cancer cells.