Colorectal cancer cell (CRC) increases the utilization of glucose and decreases the oxidation of butyrate, which is a primary energy source for non‐cancerous colonocytes. Butyrate is a short‐chain fatty acid that is a bacterial‐derived fiber fermentation product. It takes years for the colorectal adenoma to manifest as it progresses toward invasive carcinoma. Within this timeframe, the adenoma must acquire key genomic and metabolic modifications that promote tumor growth and progression. Understanding the metabolic shift mechanisms away from butyrate oxidation to glycolysis in the CRC is significant. The overexpression of the pyruvate kinase isoform M2 (PKM2) is observed in biopsies of colorectal cancer patients, which is a hallmark of cancer. Pyruvate kinase is a metabolic enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate generating ATP. PKM1 is generally expressed in adult differentiated tissues, such as normal non‐cancerous colonic tissue, where it promotes oxidative metabolism. In contrast, PKM2 is expressed in proliferating cells, including colorectal cancer cells, where it enhances aerobic glycolysis. However, the function of PKM2 in colorectal cancer tumorigenesis remains controversial. Our preliminary studies suggest that PKM2 drives colorectal metabolism away from butyrate and toward glucose utilization. A stable knockdown of PKM2 in colorectal cancer cells increased the oxidation of butyrate. The major hypothesis for this project is that through enhancing glucose utilization and suppressing butyrate, utilization PKM2 promotes colorectal tumor progression. Here, we demonstrate that, when expressed rather than PKM2, the PKM1 increases butyrate oxidation in cancerous colonocytes.
Support or Funding Information
USDA R011770176
In ulcerative colitis (UC) and colorectal cancer (CRC), the colonocyte undergoes a metabolic shift. This metabolic shift involves a decrease in the oxidation of the microbial‐derived short‐chain fatty acid, butyrate. The factors that promote this metabolic shift in these diseases are not fully understood. Previously, we showed interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine that is elevated in UC and CRC, decreased the oxidation of butyrate in CRC cells. Experiments identified p38, a mitogen‐activated protein kinase, mediates the diminished butyrate oxidation caused by IL‐1β. We have identified tumor necrosis factor a (TNF‐a) as another pro‐inflammatory cytokine that decreases butyrate oxidation in colorectal cells. The hypothesis is that IL‐1β or TNF‐a drives metabolic shifts in colonocytes that promote disease via the p38 signaling pathway. Both IL‐1β and TNF‐a activate p38 (phosphorylation of p38) in colorectal cancer cells. Next, we utilized the Seahorse XF24 Analyzer to measure butyrate oxidation with and without IL‐1β or TNF‐a treatment. The oxidation of butyrate was lower in cells treated with IL‐1β or TNF‐a compared to untreated controls. Furthermore, IL‐1β or TNF‐a showed a shift in metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. CRC cells treated with IL‐1β or TNF‐a showed increased extracellular acidification rate compared to controls, which indicates that IL‐1β or TNF‐a induces a switch toward glycolysis. Inhibition of p38 or knockdown of p38 decreased IL‐1β or TNF‐a ability to suppress butyrate oxidation. These data provide a mechanism by which cytokines, through p38, regulate metabolism in the diseased colonocyte.
Support or Funding Information
USDA R011770176
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.