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代谢流技术在结肠癌谷氨酰胺代谢研究中的应用

PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is one of the most frequently mutated oncogene in human cancers. Here we show that oncogenic PIK3CA mutations reprogram glutamine metabolism by up-regulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells through an AKT-independent PDK1-RSK2-ATF4 signaling axis, thereby rendering them addicted to glutamine. With [U-13C5]glutamine flux tracing in colorectal cancer (CRC) models in vitro and in vivo, PIK3CA mutations significantly enhance glutamine metabolism into TCA cycle in tumors comparing with normal colon tissues or PIK3CA Wild-type tumors. Glutamine metabolism inhibitors CB-839 or AOA preferentially inhibits xenograft growth of PIK3CA mutant, but not PIK3CA wild-type, CRCs. Moreover, combination of CB-839 with 5-FU induces CRC tumor regression. These data suggest that CRC utilize glutamine to replenish the TCA cycle and that targeting glutamine metabolism may be an effective approach to treat PIK3CA mutant CRCs.

287 2020-11-06

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