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.
Highlights
Aerobic glycolysis, known as Warburg effect, has been established as a hallmark of cancer cells [1]
We found that Oleanolic acid (OA) can suppress aerobic glycolysis by suppressing pyruvate kinase M2 (PKM2) expression and affected PKM mRNA splicing through mTOR/c-Myc/hnRNP signaling
To identify the mechanisms that OA affected aerobic glycolysis, we subsequently evaluated the changes in the expression level of PKM1 and PKM2 in cancer cells treated with OA
Summary
Known as Warburg effect, has been established as a hallmark of cancer cells [1]. Almost all types of cancer cells change their metabolism by increasing glycolysis and suppressing mitochondrial oxidative phosphorylation, even under normoxic conditions ( defined as aerobic glycolysis) [2]. Highly proliferating cancer cells meet their requirements for cellular building materials by switching their metabolism from oxidative phophorylation to glycolysis, ATP production is less efficient in glycolytic process. Cancer cells utilize PKM2 to accumulate the intermediates for the synthesis of nucleic acid and protein and maintain aerobic glycolysis [5]. Increasing PKM2 activity or switching mRNA splicing from PKM2 to PKM1 is able to suppress the Warburg effect, and compromise tumor growth [6]. The compounds that can increase the ratio of PKM1 to PKM2 have not been found
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