NDRG2通过PTEN对前列腺癌糖代谢的调节效应及其分子机制研究

The occurrence and prognosis of prostate cancer is closely related to the loss of heterozygosity of PTEN, but the molecular mechanism still need to be further investigated. Our research group discovered and cloned the tumor suppressor gene NDRG2 whose encoding protein interacts with PTEN and promotes the phosphatidylinositol-3,4,5-trisphosphate activity of PTEN, thereby inhibits PI3K/Akt pathway and metabolic reprogramming of tumor cells. In addition, our research group also discovered that PTEN loss can upregulate HK2, thereby promotes aerobic glycolysis of prostate cancer cells. On this basis, we prefer to clarify firstly the regulation of NDRG2 on glucose metabolism in prostate cancer cells via PTEN; Secondly, to analyze the molecular mechanisms about glucose metabolism regulated by NDRG2 and to clarify metabolic targets such as GLUT1, HK2, FBP1 and other molecules regulated by NDRG2 in prostate cancer cells via PTEN; Finally, to analyze the effect of NDRG2 on glucose metabolism and malignant proliferation of prostate cancer with PTEN heterozygous loss both in animals and clinical patients samples, and to explore the therapeutic value of NDRG2 on prostate cancer patients with PTEN heterozygous loss. Our study will not only further understand the biological functions of tumor suppressor PTEN and NDRG2, but also expect to discover new NDRG2-related regulation mechanism on prostate cancer caused by PTEN heterozygous loss, and provide clues for early diagnosis and treatment of prostate cancer.

前列腺癌的发生和预后与抑癌基因PTEN的杂合缺失密切相关，其分子机制有待于深入研究。本课题组发现并克隆的抑癌基因NDRG2的编码产物能够与PTEN的编码产物相互作用，并促进PTEN磷脂酰肌醇磷酸酶活性，抑制肿瘤代谢重编程。前期研究还发现：PTEN缺失导致己糖激酶HK2表达增强，从而促进前列腺癌的糖酵解。在此基础上本课题：首先明确NDRG2通过PTEN对前列腺癌糖代谢途径的调节作用；然后分析NDRG2通过PTEN调控前列腺癌糖代谢途径的分子靶点与机制；最后从动物与临床标本分析NDRG2对PTEN杂合缺失型前列腺癌糖代谢以及恶性增殖的抑制效应，并探讨其治疗价值。本研究不仅为深入理解PTEN与NDRG2的生物学功能奠定基础，而且期望发现以NDRG2为关键分子调节PTEN杂合缺失型前列腺癌代谢异常的新机制，为临床前列腺癌的诊断和治疗提供新的药物靶点。

前列腺癌的发生和发展与抑癌基因PTEN的缺失密切相关。本课题研究发现：① PTEN缺失导致前列腺癌细胞代谢重编程。代谢组学分析显示PTEN缺失导致前列腺癌细胞糖酵解增强、谷氨酰胺分解代谢增强、脂肪酸从头合成和β氧化增强，同时支链氨基酸分解代谢增强；② PTEN缺失导致前列腺癌细胞己糖激酶HK2含量增强，糖酵解增强。HK2含量的增加与PTEN缺失导致Akt/mTORC1/4EBP1信号途径的激活密切相关；③ 本课题组发现并克隆的抑癌基因NDRG2的编码产物能够与PTEN的编码产物相互作用，并促进PTEN磷脂酰肌醇磷酸酶活性，抑制蛋白激酶Akt的磷酸化修饰及其活化，从而抑制PTEN缺失型前列腺癌的代谢重编程以及前列腺癌的恶性生长与增殖。本课题研究不仅为深入理解PTEN与NDRG2的生物学功能奠定基础，而且发现了以NDRG2为关键分子调节PTEN杂合缺失型前列腺癌代谢异常的新机制，为临床前列腺癌的诊断和治疗提供新的药物靶点。