title: Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms.
abstract: Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, China; Graduate School, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Molecular Biology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
authors.forename: Leina
authors.initials: L
authors.lastname: Ma
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, China; Graduate School, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, China.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institutes of Oceanology, Chinese Academy of Sciences, Qingdao, China; Department of Pharmacology, Capital Medical University, Beijing, China.
authors.forename: Xiukun
authors.initials: X
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009828:Oleanolic Acid / Q000737:chemistry*; D010085:Oxidative Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D008565:Membrane Proteins; D009828:Oleanolic Acid; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C000619656:hnRNPA1 protein, human