Targeting glutamine metabolism network for the treatment of therapy-resistant prostate cancer

[Graham49]

Targeting glutamine metabolism network for the treatment of therapy-resistant prostate cancer

Lingfan Xu, Bing Zhao, William Butler, Huan Xu, Nan Song, Xufeng Chen, J. Spencer Hauck, Xia Gao, Hong Zhang, Jeff Groth, Qing Yang, Yue Zhao, David Moon, Daniel George, Yinglu Zhou, Yiping He & Jiaoti Huang

Oncogene (2022)Cite this article

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Abstract

Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients.