(740.4) Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes

Poster Board Number: E315

Bohye Park (University of Tennessee Knoxville), Ji Yeon Kim (University of Tennessee Knoxville), Olivia Riffey (University of Tennessee Knoxville), Antje Bruckbauer (University of Tennessee Knoxville), James McLoughlin (University of Tennessee Knoxville), Ahmed Bettaieb (University of Tennessee Knoxville), Dallas Donohoe (University of Tennessee Knoxville)

Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Butyrate is a short-chain fatty acid produced by resident bacteria in the colon and serves as the primary energy source for non-cancerous colonocytes. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate, and produces ATP. M1 and M2 are alternatively spliced isoforms of the Pkm gene. The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. We hypothesize that the PKM isoforms are involved in the shift away from butyrate oxidation towards glycolysis in CRC cells. Here, we find that PKM2 is increased and PKM1 is decreased in human colorectal carcinomas as compared to non-cancerous tissue. To test whether PKM1/2 alter colonocyte metabolism, we created a knockdown of PKM2 and PKM1 in CRC cells to analyze how butyrate oxidation and glycolysis would be impacted. We report that butyrate oxidation in CRC cells is regulated by PKM1 levels, not by PKM2. Decreased butyrate oxidation observed through knockdown of PKM1 and PKM2 is rescued through re-addition of PKM1. Diminished PKM1 lowered mitochondrial basal respiration and decreased mitochondrial spare capacity. We demonstrate that PKM1 inhibits hypoxia-inducible factor-1 alpha (HIF1α) and suppresses glycolysis. These data suggest that reduced PKM1 is, in part, responsible for increased glycolysis and diminished butyrate oxidation in CRC cells.

This work was supported by USDA NIFA (2019-67017-29261). Work performed in the Bettaieb lab is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736).