Inhibiting Glutamine Metabolism Blocks Growth of Some Colorectal Tumors

Cancer researchers have found a way to block growth of colorectal tumors that express a mutation, which enables the cancer cells to use glutamine as their primary energy source.

Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Investigators at Case Western Reserve University (Cleveland, OH, USA) searched for the molecular signaling pathway that controlled glutamine metabolism in colorectal cancer cells with and without a mutation in the PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) gene.

The investigators reported their findings in the June 20, 2016, online edition of the journal Nature Communications. They found that PIK3CA mutations reprogrammed glutamine metabolism by upregulating production of the enzyme glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type cells, PIK3CA mutant CRCs converted substantially more glutamine to alpha-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP.

In addition, the investigators found that the compound aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppressed xenograft tumor growth of CRCs with PIK3CA mutations, but not with wild-type PIK3CA.

Senior author Dr. Zhenghe Wang, professor of genetics and genome sciences at Case Western Reserve University, said, "In layman's terms, we discovered that colon cancers with PIK3CA oncogenic mutations are addicted to glutamine, a particular nutrient for cancer cells. We also demonstrated that these cancers can be starved to death by depriving glutamine with drugs."

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