乳腺癌糖酵解及非氧化戊糖磷酸代谢途径调控机理的研究

Glycolysis （Warburg effect） is the fundamental character of cancer metabolism. It provides essential material to support the rapid growth of tumor. Disturbing or reversing the tumoral glycolysis inhibits tumor growth. PI3K is one of the major regulators of cellular glycolysis and is frequently mutated in breast cancer. Studies have shown that PI3K drives breast cancer through the Warburg effect. Our previous studies have shown that PI3K promoted glycolysis and non-oxidative pentose phosphate pathway via AKT and Rac-aldolase pathways. PI3K inhibitor suppresses glycolysis and non-oxidative pentose phosphate pathway to suspend breast cancer development. We have generated PI3K inhibitor sensitive or resistant mouse breast cancer models, and revealed that PI3K no longer promoted glycolysis and non-oxidative pentose phosphate pathway in the PI3K inhibitor resistant tumor. We will compare the expression profile between the inhibitor resistant and sensitive tumors to reveal the regulation of glycolysis and non-oxidative pentose phosphate pathway beyond PI3K pathway. These studies will not only expand our knowledge of the regulation of glycolysis and non-oxidative pentose phosphate pathway, but also help designing new targeting therapy to breast cancer, as well as identifying the molecule markers for PI3K targeting therapy.

糖酵解（Warburg effect）是肿瘤代谢异常主要特征性，是支持肿瘤快速生长物质基础的保证。干扰、逆转这种代谢异常能抑制肿瘤生长。PI3K是调控细胞糖代谢的主要激酶，在乳腺癌中高频突变。研究表明PI3K主要通过Warburg effect驱动乳腺癌生长。我们发现PI3K通过AKT、Rac-aldolase等通路驱动糖酵解及非氧化戊糖磷酸途径，PI3K抑制剂显著抑制糖酵解及非氧化戊糖磷酸途径而抑制乳腺癌生长。我们建立了PI3K抑制剂敏感和耐受的小鼠乳腺癌模型；发现PI3K抑制剂耐受模型中，PI3K不再调控糖酵解及非氧化戊糖磷酸途径。我们将对比两种肿瘤表达谱的差异，鉴定调控糖酵解及非氧化戊糖磷酸途径的基因和非编码RNA，阐明其分子机理。本研究将加深对乳腺癌糖酵解及非氧化戊糖磷酸途径调控信号通路的认识，鉴定新的治疗乳腺癌的分子靶点，还有助于提出乳腺癌对PI3K抑制剂治疗敏感性的分子标志谱。

本课题在PI3K通路可调控糖酵解和非氧化戊糖磷酸途径的基础上，利用乳腺癌细胞模型、动物模型和乳腺癌组织标本，发现Rac1可激活非氧化戊糖磷酸途径，并通过分别激活醛缩酶A和ERK信号通路增强核苷代谢及DNA损伤修复，从而诱导了乳腺癌的化疗耐药。并且，本课题通过开发了一种内体pH响应纳米颗粒系统，可将Rac1 siRNA与化疗药物体内递送至乳腺肿瘤，有效恢复肿瘤对化疗药物的敏感性。