Abstract
The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5+ intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2ΔLgr5-Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2ΔLgr5-Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2ΔLgr5-Tx mice while PKM2ΔLgr5-Veh mice had low- and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5+ ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5+ cells obtained from colon polyps of PKM2ΔLgr5-Tx mice was significantly increased when compared with PKM2ΔLgr5-Veh mice. Cancer organoids from PKM2ΔLgr5-Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.
Highlights
Pyruvate kinase (PK) is involved in the final step of glycolysis by transferring the phosphate group from phosphoenolpyruvate to ADP and producing pyruvate and ATP
We found that mRNA levels of pyruvate kinase M2 isoform (PKM2), but not PKM1, were highly expressed in both human normal and cancer colon tissues
In colorectal cancer (CRC) patients, the expression of Lgr[5], the cancer stem cell marker, was positively correlated with PKM expression (Fig. 1f). These results suggest that PKM2 expression is increased during inflammation-induced CRC development, either as a consequence of oncogenic transformation or as a metabolic oncogene
Summary
Pyruvate kinase (PK) is involved in the final step of glycolysis by transferring the phosphate group from phosphoenolpyruvate to ADP and producing pyruvate and ATP. A recent study showed that depletion of PKM2 did not affect c-MYC-induced liver tumor formation[12]. These results challenge the idea that PKM2 is essential in tumorigenesis. Www.nature.com/scientificreports cancer-related regulatory genes, caused by chronic inflammation and oxidative stress, result in abnormal growth of intestinal epithelial cells and the pathogenesis of colitis-associated CRC18,19. When Lgr5-GFP mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce inflammation-driven CRC, 75% of the polyps arose from GFP+Lgr5+ sites[24] These results suggest that Lgr[5] acts as a marker for cancer stem cells (CSC)
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