Protein Phosphatase 2A Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling

Abstract

Background: The Warburg effect is closely associated malignant phenotypes and poor prognosis in cancer patients. PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase that functions as a tumor suppressor in a variety of human cancers. However, the relationship between PP2A and the Warburg effect has yet to be fully understood. Methods: The expression profile of two endogenous inhibitors of PP2A, SET and CIP2A, are detected by real-time qPCR. Loss-of-function and gain-of-function are performed to demonstrate the roles of PP2A in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches are used to uncover the underlying mechanism. Results: In this study, we find that SET and CIP2A are overexpressed in gastric cancer and associates a decreased PP2A activity. Pharmacological activation of PP2A with FTY-720 and DT-061 significantly reduces gastric cancer cell proliferation and glycolytic ability. Importantly, inhibition of PP2A activity by genetic silencing of PPP2R5A induces a growth advantage, which can be largely compromised by addition of the glycolysis inhibitor 2-Deoxy-D-glucose, suggesting a glycolysis-dependent effect of PP2A in gastric cancer. Mechanistically, the well known transcription factor and glycolysis regulator c-Myc is discovered as the functional mediator of PP2A in regulating cell glycolysis. Ectopic expression of a phosphorylation-mutant c-Myc resistant to PP2A (MycT58A) restores the inhibitory effect of FTY-720 and DT-061 on the lactate production and glucose uptake. Furthermore, there is a close association between SET and CIP2A expression and c-Myc gene signatures in gastric cancer samples. Conclusions: This study provides strong evidence of the involvement of PP2A in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.