Abstract B03: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers

Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Using isogenic cell lines expressing either wild-type (WT) or oncogenic mutant allele of PIK3CA, we demonstrated that colorectal cancer cells harboring PIK3CA mutations are more dependent on glutamine to grow. In contrast, the isogenic PIK3CA WT and mutant cell lines did not show differential sensitivity to glucose deprivation. Through gene expression analyses, we showed that glutamate pyruvate transaminase 2 (GPT2) is up-regulated in the colorectal cancer cell lines with PIK3CA mutations compared to the isogenic cell lines expressing WT PIK3CA. We demonstrated that induction of GPT2 by mutant p110 alpha is necessary and sufficient to render colorectal cancer cells dependent on glutamine. Moreover, aminooxyacetate, which inhibits enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumor growth of colorectal cancers with PIK3CA mutations, but not colorectal cancers with WT PIK3CA. Thus our data suggest that targeting glutamine metabolism may be an effective approach to treat colorectal cancer patients harboring PIK3CA mutations. Mutant p110 alpha up-regulates ...

Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wang, Z. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research