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: Jia Liu, Ning Wu, Leina Ma, Ming Liu, Ge Liu, Yuyan Zhang, Xiukun Lin
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e91606 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24626155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carrier Proteins
• Heterogeneous Nuclear Ribonucleoprotein A1
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B
• Membrane Proteins
• Protein Isoforms
• Proto-Oncogene Proteins c-myc
• Thyroid Hormones
• hnRNPA1 protein, human
• thyroid hormone-binding proteins
• Oleanolic Acid
• Pyruvate Kinase

Topics

• Antineoplastic Agents (chemistry)
• Breast Neoplasms (metabolism)
• Carrier Proteins (metabolism)
• Cell Line, Tumor (drug effects)
• Female
• Gene Expression Regulation, Neoplastic
• Glycolysis (drug effects)
• Heterogeneous Nuclear Ribonucleoprotein A1
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B (metabolism)
• Humans
• MCF-7 Cells (drug effects)
• Male
• Membrane Proteins (metabolism)
• Mitochondria (metabolism)
• Oleanolic Acid (chemistry)
• Oxidative Phosphorylation
• Prostatic Neoplasms (metabolism)
• Protein Isoforms (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Pyruvate Kinase (metabolism)
• Thyroid Hormones (metabolism)