Mechanisms of metabolic reprogramming by PIK3CA oncogenic mutations

PIK3CA致癌突变的代谢重编程机制

• 批准号: 9914225
• 负责人: Henri Brunengraber
• 金额: $ 37.98万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-20 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914225
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Alleles; Amino Acids; Aminooxyacetate; Apoptosis; Autophagocytosis; Cancer Biology; Cancer Etiology; Catalytic Domain; Cell Cycle Progression; Cell Line; Cells; Cessation of life; Citrates; Citric Acid Cycle; Clinical; Colorectal Cancer; Cultured Cells; Data; Dependence; Development; Disease; Enzymes; Event; Foundations; Future; GPT2 gene; Gene Expression; Gene Expression Profiling; Genetic Transcription; Glutamates; Glutamine; Glutarates; Goals; Growth; Human; In Vitro; Intervention; Intestinal Neoplasms; Knock-in Mouse; Lead; Lipids; Malignant Neoplasms; Metabolic; Metabolism; Molecular; Mutate; Mutation; Nutrient; Oncogenic; PDPK1 gene; PIK3CA gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Precision therapeutics; Probability; Proteins; Proto-Oncogene Proteins c-akt; Pyruvate; Resistance; Signal Pathway; Signal Transduction; Solid; Specimen; Techniques; Testing; Text; Therapeutic; Transaminases; Treatment Efficacy; Tumor-Derived; United States; Warburg Effect; Xenograft procedure; base; cancer cell; cancer therapy; cell growth; cell type; clinical efficacy; colon cancer cell line; colon cancer patients; colorectal cancer treatment; deprivation; driving force; effective therapy; experimental study; in vivo; inhibitor/antagonist; innovation; knock-down; metabolic profile; mutant; novel; novel therapeutics; overexpression; public health relevance; stable isotope; success; targeted agent; targeted treatment; transcription factor; tumor growth; tumor heterogeneity; tumor metabolism; tumor xenograft

 DESCRIPTION (provided by applicant): Metabolic reprogramming is one of the hallmarks of cancer. The "Warburg effect" and glutamine dependency are two well-known metabolic reprogramming events that occur in cancer cells. It has long been known that most cancer cells are dependent on glutamine to grow. However, the mechanisms by which cancer cells become dependent on glutamine are not well understood. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase, is frequently mutated in a variety of human cancers including 20 to 30% of colorectal cancers. Our preliminary studies demonstrate that colorectal cancer cells harboring oncogenic PIK3CA mutations are more dependent on glutamine, suggesting that mutant PIK3CA may be a driving force that reprograms glutamine metabolism in cancer cells. Moreover, our gene expression analyses show that expression levels of GPT2, an enzyme that catalyzes conversion of glutamate to α-keto-glutarate, are up- regulated in colorectal cancer cells harboring PIK3CA mutations. Knockdown of GPT2 makes PIK3CA mutant cell growth less dependent on glutamine, whereas overexpression of GPT2 renders PIK3CA wild-type (WT) cell more sensitive to glutamine deprivation. Remarkably, we found that aminooxyacetate (AOA), a small compound which inhibits GPT2 enzymatic activity, suppresses xenograft tumor growth of colorectal cancers harboring oncogenic PIK3CA mutations, but not WT PIK3CA. These results lead us to hypothesize that the oncogenic PIK3CA/p110α mutant-GPT2 axis reprograms colorectal cancer metabolism and thus renders cancer cells dependent on glutamine. We propose that targeting glutamine metabolism will be an effective treatment for colorectal cancer patients harboring PIK3CA mutations. To test our hypotheses and to elucidate the molecular mechanisms by which mutant p110α reprograms cancer metabolism, we propose the following aims: (1) delineate the signaling pathway by which mutant p110α up-regulates GPT2 expression; (2) determine how the p110α-GPT2 axis reprograms glutamine metabolism in colorectal cancer; and (3) determine in preclinical models if targeting glutamine metabolism is an effective treatment for colorectal cancers harboring PIK3CA mutations. Our proposed studies investigate an innovative concept that oncogenic PIK3CA mutations reprogram colorectal cancer metabolism and render cancers dependent on glutamine. Moreover, our studies may provide a novel precision therapy that targets glutamine metabolism in colorectal cancer patients harboring PIK3CA mutations. Given that PIK3CA is frequently mutated in a variety of human cancers, we expect that our proposed studies will have broader conceptual and therapeutic impacts that extend beyond colorectal cancer.

 描述（由申请人提供）：代谢重编程是癌症的标志之一。 “瓦尔堡效应”和谷氨酰胺依赖性是癌细胞中发生的两个众所周知的代谢重编程事件。人们早就知道大多数癌细胞依赖谷氨酰胺生长。然而，癌细胞依赖谷氨酰胺的机制尚不清楚。 PIK3CA 编码磷脂酰肌醇 3-激酶的 p110α 催化亚基，在多种人类癌症中经常发生突变，其中包括 20% 至 30% 的结直肠癌。我们的初步研究表明，携带致癌 PIK3CA 突变的结直肠癌细胞更依赖谷氨酰胺，这表明突变的 PIK3CA 可能是重新编程癌细胞中谷氨酰胺代谢的驱动力。此外，我们的基因表达分析表明，GPT2（一种催化谷氨酸转化为α-酮戊二酸的酶）的表达水平在携带 PIK3CA 突变的结直肠癌细胞中上调。 GPT2 的敲低使 PIK3CA 突变细胞生长对谷氨酰胺的依赖性降低，而 GPT2 的过度表达使 PIK3CA 野生型 (WT) 细胞对谷氨酰胺剥夺更加敏感。值得注意的是，我们发现氨氧乙酸（AOA）是一种抑制 GPT2 酶活性的小化合物，可抑制携带致癌 PIK3CA 突变的结直肠癌的异种移植肿瘤生长，但不能抑制 WT PIK3CA。这些结果使我们推测致癌的 PIK3CA/p110α 突变体 - GPT2 轴重新编程结直肠癌代谢，从而使癌细胞依赖于谷氨酰胺。我们认为，针对谷氨酰胺代谢将是携带 PIK3CA 突变的结直肠癌患者的有效治疗方法。为了检验我们的假设并阐明突变体p110α重编程癌症代谢的分子机制，我们提出以下目标：（1）描绘突变体p110α上调GPT2表达的信号通路； (2)确定p110α-GPT2轴如何重新编程结直肠癌中的谷氨酰胺代谢； (3) 在临床前模型中确定针对谷氨酰胺代谢是否是治疗携带 PIK3CA 突变的结直肠癌的有效方法。我们提出的研究调查了一个创新概念，即致癌 PIK3CA 突变会重新编程结直肠癌代谢并使癌症依赖于谷氨酰胺。此外，我们的研究可能提供一种针对携带 PIK3CA 突变的结直肠癌患者的谷氨酰胺代谢的新型精准疗法。鉴于 PIK3CA 在多种人类癌症中经常发生突变，我们预计我们提出的研究将产生更广泛的概念和治疗影响，超越结直肠癌。