AMPK对原癌基因PIKE-A的反向调控作用、机制及其在神经胶质瘤发生发展转归中的意义

多型性胶质母细胞瘤(GBM)是中枢神经系统发病率和致死率最高的恶性肿瘤，其发病机制不清楚，治疗靶点不明确。能量感受器AMPK是抑癌基因，调节mTOR信号通路抑制细胞增殖和肿瘤生长。原癌基因PIKE-A通过激活PI3K-Akt信号通路促进细胞增殖、转移和转化。我们前期研究结果表明，PIKE-A与AMPK直接结合，抑制AMPK的活性和信号通路而促进GBM细胞增殖。进一步又发现AMPK能反馈性的使得PIKE-A蛋白发生丝氨酸/苏氨酸残基磷酸化，但这种磷酸化修饰对PIKE-A的促进GBM恶性表型的生物学意义以及分子机制还不清楚。本项目拟在GBM细胞和动物模型中深入研究AMPK对PIKE-A的反向调控作用对细胞增殖、细胞周期和衰老等的影响及其分子机制，并利用大量GBM病人肿瘤组织标本探讨其在GBM发生发展转归中的意义，为鉴定GBM治疗靶点提供理论依据，为GBM的预后和个性化精准治疗提供新的思路。

Glioblastoma multiforme (GBM), known as glioblastoma and grade IV astrocytoma, is one of the most common, aggressive and malignant brain tumors in the central nervous system. While there have been considerable advances in the multimodality treatment of GBM in the last few decades, only minimal improvements in the median survival time and the 5-year survival rate occurred. Therefore, uncovering the tumorigenesis mechanism of GBM is essential for finding novel treatments to improve patient prognosis. The AMP-activated protein kinase (AMPK) functions to monitor and maintain energy homeostasis at the cellular and organism level. AMPK was perceived historically primarily as a component of the LKB1/STK11 tumor suppressor cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppressor. PIKE-A acts as a proto-oncogene, is overexpressed in various human cancer samples and promotes cell growth, migration, invasion and transformation through Akt activation. Our preliminary studies show that PIKE-A directly interacts with AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. Thus, these findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression. Moreover, we found that AMPK feeds back and phosphorylates PIKE-A. However, the biological significance of this event remains elusive. We hypothesize that AMPK restroregulates PIKE, inhibits CDK4 activity and suppresses cell proliferation and tumor growth in glioblastoma. The objective of this proposed research is to determine the physiological functions of AMPK phosphorylated-PIKE-A in glioblastoma. Characterization of the molecular mechanisms by AMPK and PIKE-A in the cell proliferation machinery in glioblastoma not only leads to a better understanding of glioblastoma development but also promises to provide effective individuation and systematic treatment in clinic.