Mechanisms of metabolic reprogramming by PIK3CA oncogenic mutations

PIK3CA致癌突变的代谢重编程机制

基本信息

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
项目类别：
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

项目摘要

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“瓦伯格效应”和谷氨酰胺依赖性是癌细胞中发生的两种众所周知的代谢重编程事件。人们早已知道大多数癌细胞是依赖性的。然而，癌细胞依赖谷氨酰胺的机制尚不清楚，PIK3CA 编码 p110α 催化亚基。磷脂酰肌醇 3-激酶在多种人类癌症中经常发生突变，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于谷氨酰胺，这表明突变的 PIK3CA 可能是一个驱动力。此外，我们的基因表达分析表明，GPT2（一种酶）的表达水平催化谷氨酸转化为 α-酮戊二酸，在携带 PIK3CA 突变的结直肠癌细胞中上调，GPT2 的敲除使 PIK3CA 突变细胞生长更少依赖于谷氨酰胺，而 GPT2 的过度表达使 PIK3CA 野生型 (WT) 细胞更加依赖。对谷氨酰胺缺乏敏感值得注意的是，我们发现氨氧乙酸（AOA）是一种抑制谷氨酰胺的小化合物。 GPT2 酶活性可抑制含有致癌 PIK3CA 突变的结直肠癌异种移植肿瘤生长，但不能抑制 WT PIK3CA。这些结果使我们发现，致癌 PIK3CA/p110α 突变体-GPT2 轴会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 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 如何上调 GPT2 表达； -GPT2轴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靶向谷氨酰胺代谢是否是结直肠癌的有效治疗方法我们提出的研究调查了一种创新概念，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，我们的研究可能会提供一种针对携带 PIK3CA 突变的结直肠癌患者的谷氨酰胺代谢的新型精准疗法。 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。