Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer

• Published in: Scientific reports Vol. 9; no. 1; p. 6212
• Main Authors: Kim, Yeji, Lee, Yong-Soo, Kang, Sung Wan, Kim, Seungil, Kim, Tae-Young, Lee, Su-Hyun, Hwang, Sung Wook, Kim, Jihun, Kim, Eun Na, Ju, Jin-Sung, Park, Yun-Yong, Kweon, Mi-Na
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.04.2019; Nature Publishing Group
• Subjects: 13; 13/1; 13/100; 13/106; 13/31; 13/51; 14/19; 14/63; 631/67/2327; 692/4020/1503/1504/1885/1393; Adenocarcinoma; Animals; Body weight; Carrier Proteins - metabolism; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Clonal deletion; Cohort Studies; Colitis, Ulcerative - complications; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - complications; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Models, Animal; Dysplasia; Energy metabolism; Glycolysis; Humanities and Social Sciences; Humans; Inflammatory bowel disease; Intestine; Intestines - pathology; Male; Membrane Proteins - metabolism; Metabolism; Metabolites; Mice; Mitochondria; multidisciplinary; Organoids; Oxygen consumption; Polyps; Pyruvate kinase; Pyruvate Kinase - antagonists & inhibitors; Pyruvate Kinase - metabolism; Pyruvic acid; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Stem Cells - metabolism; Tamoxifen; Tamoxifen - pharmacology; Thyroid Hormone-Binding Proteins; Thyroid Hormones - metabolism; Ulcerative colitis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42707-8

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 (PKM2 ΔLgr5 -Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2 ΔLgr5 -Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2 ΔLgr5 -Tx mice while PKM2 ΔLgr5 -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 PKM2 ΔLgr5 -Tx mice was significantly increased when compared with PKM2 ΔLgr5 -Veh mice. Cancer organoids from PKM2 ΔLgr5 -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.