Tumor cells are usually considered defective in mitochondrial respiration, but human non-small cell lung cancer (NSCLC) tumor tissues are shown to have enhanced glucose oxidation relative to adjacent benign lung. Here, we reported that oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) inhibited glycolysis and promoted oxidative metabolism in NSCLC cells. CIP2A bound to pyruvate kinase M2 (PKM2) and induced the formation of PKM2 tetramer, with serine 287 as a novel phosphorylation site essential for PKM2 dimer-tetramer switching. CIP2A redirected PKM2 to mitochondrion, leading to upregulation of Bcl2 via phosphorylating Bcl2 at threonine 69. Clinically, CIP2A level in tumor tissues was positively correlated with the level of phosphorylated PKM2 S287. CIP2A-targeting compounds synergized with glycolysis inhibitor in suppressing cell proliferation in vitro and in vivo. These results indicated that CIP2A facilitates oxidative phosphorylation by promoting tetrameric PKM2 formation, and targeting CIP2A and glycolysis exhibits therapeutic potentials in NSCLC.

肿瘤细胞通常被认为存在线粒体呼吸缺陷，但人类非小细胞肺癌 (NSCLC) 肿瘤组织与邻近的良性肺相比，葡萄糖氧化增强。在这里，我们报道了蛋白磷酸酶 2A 的癌蛋白癌性抑制剂 (CIP2A) 抑制 NSCLC 细胞中的糖酵解并促进氧化代谢。 CIP2A 与丙酮酸激酶 M2 (PKM2) 结合并诱导 PKM2 四聚体的形成，其中丝氨酸 287 作为 PKM2 二聚体-四聚体转换所必需的新型磷酸化位点。 CIP2A将PKM2重定向至线粒体，通过磷酸化Bcl2的苏氨酸69导致Bcl2上调。临床上，肿瘤组织中的CIP2A水平与磷酸化PKM2 S287的水平呈正相关。 CIP2A 靶向化合物与糖酵解抑制剂协同作用，在体外和体内抑制细胞增殖。这些结果表明，CIP2A 通过促进四聚体 PKM2 形成来促进氧化磷酸化，并且靶向 CIP2A 和糖酵解在 NSCLC 中表现出治疗潜力。