解码Cdc25A在肿瘤能量代谢中的作用

Cdc25A is an instrumental protein phosphatase in cell cycle progression that is overexpressed in many types of human cancer. However, the role of Cdc25A in cancer metabolism is unclear, and although its role in the regulation of Cdk dephosphorylation is well established, Cdc25A may contain other important cellular substrates. We revealed that EGF stimulation induces PKM2 phosphorylation in the cytosol, which is essential for the nuclear translocation of PKM2. In the nucleus, PKM2 is dephosphorylated by interacting with Cdc25A, which is required for EGF-induced β-catenin transactivation. We hypothesize that Cdc25A regulates cancer metabolism and tumor progression by dephosphorylating nuclear PKM2. To test this hypothesis, we will pursue three specific aims: (1) To further elucidate the mechanisms underlying Cdc25A-dependent PKM2 dephosphorylation and the subsequent activation of β-catenin; (2) To determine the role of Cdc25A-dependent PKM2 dephosphorylation in the Warburg effect, tumor cell proliferation, and brain tumorigenesis; and (3) To determine the clinical significance of Cdc25A-dependent PKM2 dephosphorylation in human glioma. The proposed research is significant because it could lead to pharmaceutical approaches to interrupt cancer metabolism by blocking the function of Cdc25A; this would, in turn, improve the efficacy of human cancer treatment.

Cdc25A是在细胞周期中起关键作用的蛋白磷酸酶，它在多种肿瘤中高表达。然而，Cdc25A在肿瘤能量代谢中的作用还不清楚。我们的研究表明，EGF可诱导胞浆中丙酮酸激酶M2（PKM2）磷酸化，促使PKM2进入细胞核。在细胞核中，PKM2与Cdc25A结合并被其去磷酸化，这一过程对于EGF诱导的β-catenin活化是必须的。因此，我们提出假说，Cdc25A通过去磷酸细胞核中的PKM2从而调节肿瘤能量代谢和肿瘤进展。要验证这一假说，我们提出以下目标：（1）进一步阐释Cdc25A依赖的PKM2去磷酸化以及β-catenin激活的分子机制；（2）明确Cdc25A依赖的PKM2去磷酸化在Warburg效应、肿瘤细胞生长和胶质瘤形成中的作用；（3）明确Cdc25A依赖的PKM2去磷酸化在胶质瘤中的临床意义。这项研究有助于开发药物，通过阻断Cdc25A的功能抑制肿瘤能量代谢，最终提高肿瘤临床治疗效果。

许多类型的肿瘤细胞过表达双重特异性磷酸酶Cdc25A。Cdc25A使细胞周期蛋白依赖性激酶去磷酸化并调节细胞周期，但Cdc25A其他的底物及其相关的功能尚不明确。我们在这个课题中揭示了EGFR的激活导致Cdc25A在Y59氨基酸残基位点的磷酸化，并且该磷酸化由c-Src介导。磷酸化的Cdc25A可与核丙酮酸激酶M2（PKM2）相互作用。 Cdc25A介导了 PKM2在S37氨基酸残基位点的去磷酸化，并促进了PKM2依赖性β-连环蛋白反式激活和c-Myc调控的糖酵解基因GLUT1，PKM2和LDHA以及CDC25A的表达；因此，Cdc25A可以正反馈调节自身的表达。 Cdc25A介导的PKM2去磷酸化可促进Warburg效应，细胞增殖和脑肿瘤发生。我们还发现在胶质母细胞瘤标本中Cdc25A Y59磷酸化，Cdc25A以及PKM2之间存在正相关性。此外，Cdc25A Y59的水平磷酸化与神经胶质瘤恶性程度和预后相关。这些发现揭示了Cdc25A在控制细胞代谢以及EGFR促进的肿瘤发生中的重要作用。