Aerobic glycolysis, also known as the Warburg effect, has emerged as a hallmark of cancer and is associated with tumor progression and unfavorable clinical outcomes 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 in gastric cancer has yet to be fully understood. In this study, the expression profile of two endogenous inhibitors of PP2A, SET and CIP2A, in gastric cancer, were analyzed by real-time quantitative polymerase chain reaction. Loss-of-function and gain-of-function studies were performed to investigate the roles of PP2A in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches were employed to uncover the underlying mechanisms. The results showed that SET and CIP2A were overexpressed in gastric cancer and associated with a decreased PP2A activity. Pharmacological activation of PP2A with FTY-720 and DT-061 in two gastric cancer cell lines significantly reduced gastric cancer cell proliferation and glycolytic ability. Importantly, inhibition of PP2A activity by genetic silencing of PPP2R5A resulted in a growth advantage, which can be largely compromised by the 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 was discovered as the functional mediator of PP2A in regulating cell glycolysis. Ectopic expression of a phosphorylation-mutant c-Myc resistant to PP2A (MycT58A) restored the inhibitory effect of FTY-720 and DT-061 on lactate production and glucose uptake. Furthermore, there was a close association between SET and CIP2A expression and c-Myc gene signatures in gastric cancer samples. Collectively, 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.

有氧糖酵解，也称为 Warburg 效应，已成为癌症的标志，并且与癌症患者的肿瘤进展和不良临床结果有关。PP2A 是一种高度保守的真核丝氨酸/苏氨酸蛋白磷酸酶，在多种人类癌症中起肿瘤抑制因子的作用。然而，PP2A与胃癌Warburg效应之间的关系尚未完全了解。在这项研究中，通过实时定量聚合酶链反应分析了两种内源性 PP2A 抑制剂 SET 和 CIP2A 在胃癌中的表达谱。进行功能丧失和功能获得研究以研究 PP2A 在胃癌细胞增殖和糖酵解中的作用。细胞生物学、分子学、和生化方法被用来揭示潜在的机制。结果表明，SET 和 CIP2A 在胃癌中过表达，并且与 PP2A 活性降低有关。FTY-720 和 DT-061 在两种胃癌细胞系中对 PP2A 的药理学激活显着降低了胃癌细胞增殖和糖酵解能力。重要的是，通过 PPP2R5A 的基因沉默抑制 PP2A 活性导致了生长优势，这可能会因添加糖酵解抑制剂 2-脱氧-D-葡萄糖而在很大程度上受到损害，这表明 PP2A 在胃癌中具有糖酵解依赖性作用。从机制上讲，众所周知的转录因子和糖酵解调节因子 c-Myc 被发现是 PP2A 调节细胞糖酵解的功能介质。抗 PP2A 的磷酸化突变体 c-Myc (MycT58A) 的异位表达恢复了 FTY-720 和 DT-061 对乳酸生成和葡萄糖摄取的抑制作用。此外，SET 和 CIP2A 表达与胃癌样本中的 c-Myc 基因特征之间存在密切关联。总的来说，这项研究提供了 PP2A 参与 Warburg 效应的有力证据，并表明它可能是一种靶向胃癌肿瘤代谢的新型抗肿瘤策略。