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 p110? 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 ?-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/p110? 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 p110? reprograms cancer metabolism, we propose the following aims: (1) delineate the signaling pathway by which mutant p110? up-regulates GPT2 expression; (2) determine how the p110?-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.
Colorectal cancer is the second most common cause of cancer deaths in the United States, with 150,000 new cases and 55,000 deaths per year. Advances in understanding the molecular pathogenesis of this disease are fundamental to our understanding of cancer development and successful clinical intervention. It has long been known that cancer cells are dependent on certain nutrients to grow. Our proposed studies will provide novel understanding to how cancer cells become dependent on an amino acid called glutamine. Most importantly, we will investigate whether deprivation of glutamine in cancer cells by a drug will starve cancer cells to death, thereby providing a novel therapy to treat colorectal cancer patients.
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