Implications for Ulcerative Colitis and Colorectal Cancer: Role of Pyruvate Kinase M2 in Regulating the Oxidation of Fiber-derived Butyrate in the Diseased Colonocyte (OR04-04-19)

Objectives Dietary fiber has been proposed to protect against colorectal cancer. Butyrate, a fiber metabolite that is produced by bacteria in the colon, is known to inhibit cell proliferation and promote cell differentiation, while also inducing apoptotic cell death in colorectal cancer cells at physiologically relevant concentrations. Unlike the majority of cells in the human body that prefer utilizing glucose, non-cancerous colonocytes use butyrate as their primary energy source. However, colorectal cancer cells shift away from utilizing butyrate towards glucose (the Warburg effect). A decrease in butyrate utilization by the colonocyte has been reported in ulcerative colitis (UC) and colorectal cancer (CRC). In both of these diseases, the protein called Pyruvate Kinase Isoform M2 (PKM2) is a factor that has been found to be elevated in colonocytes and is known to catalyze a key step in glycolysis. We hypothesize that upregulation of PKM2 in ulcerative colitis and colorectal cancer results in diminished butyrate oxidation, and increased glucose utilization in colonocytes. Methods Mitochondrial function, substrate utilization will be analyzed in several colorectal cell lines, isolated colonocytes, or colonocytes grown in 3-D culture where PKM2 is knocked down, knocked-out, or overexpressed. An in vivo mouse model of colitis will be used to study the impact of PKM2 in the injury and repair process. Results Knockdown of PKM2 in cancerous colonocytes was associated with reduced proliferation and increased apoptosis. Butyrate oxidation was also increased in PKM2 knockdown cells. PKM2 regulated mitochondrial function and impacted the expression of uncoupling proteins (UCPs). Elevated PKM2 in primary colonocytes was associated with diminished butyrate utilization. Finally, conditional knockout of PKM2 in the colon resulted inhibited DSS-induced colitis. Conclusions These results show an important role for PKM2 in promoting ulcerative colitis and colorectal cancer through shifting colonocyte metabolism away from butyrate utilization. Funding Sources University of Tennessee - Start-up Funds.