Deciphering the role of Cdc25A in cancer metabolism.

 描述（由申请人提供）：Cdc 25 A是细胞周期进程中的一种工具性蛋白磷酸酶，在许多类型的人类癌症中过表达。然而，Cdc 25 A在癌症代谢中的作用尚不清楚，尽管其在Cdk去磷酸化调节中的作用已得到充分确立，但Cdc 25 A可能含有其他重要的细胞底物。我们发现，EGF刺激诱导PKM 2磷酸化的胞质溶胶中，这是必不可少的PKM 2的核转位。在细胞核中，PKM 2通过与Cdc 25 A相互作用而被去磷酸化，这是EGF诱导的β-连环蛋白反式激活所必需的。我们推测Cdc 25 A通过去磷酸化核PKM 2来调节癌症代谢和肿瘤进展。为了验证这一假设，我们将进行三个具体的目标：（1）进一步阐明Cdc 25 A依赖的PKM 2去磷酸化和随后的β-catenin激活的机制：（2）确定Cdc 25 A依赖的PKM 2去磷酸化在瓦尔堡效应、肿瘤细胞增殖和脑肿瘤发生中的作用;（3）探讨Cdc 25 A依赖的PKM 2去磷酸化在人脑胶质瘤中的临床意义。这项研究意义重大，因为它可能导致通过阻断Cdc 25 A的功能来中断癌症代谢的药物方法;这反过来又会提高人类癌症治疗的疗效。

 DESCRIPTION (provided by applicant): 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 ß-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 ß-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.