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

Oncogene volume 41, pages 1140–1154 (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.

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Fig. 1: Glutamine carbon and nitrogen are required equivalently for tumor survival in advanced PCa.
Fig. 2: Glutamine nitrogen is largely enriched in nucleotide biosynthesis.
Fig. 3: Glutamine carbon is associated with glutamine nitrogen in building pyrimidine rings in PCa.
Fig. 4: CAD plays a predominant role in advanced PCa.
Fig. 5: Reciprocal regulation between glutamine carbon and nitrogen metabolism in PCa.
Fig. 6: Synergistic effect of CAD and GLS1inhibtion.
Fig. 7: PI3K-AKT signaling phosphorylates CAD in advanced PCa.

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Acknowledgements

This work was supported by DOD-W81XWH-19-1-0411 (JH), DOD-W81XWH2110034 (LX), K99-K99CA237618 (XG), Prostate Cancer Foundation Movember Valor Challenge Award (2018).

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Author notes

  1. Huan Xu

    Present address: Department of Urology, Shanghai Ninth People’s Hospital, Shanghai, China

  2. Nan Song

    Present address: Department of Urology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China

Authors and Affiliations

  1. Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA

    Lingfan Xu, Bing Zhao, William Butler, Huan Xu, Nan Song, Xufeng Chen, J. Spencer Hauck, Hong Zhang, Jeff Groth, Yue Zhao, David Moon, Yiping He & Jiaoti Huang

  2. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA

    Xia Gao & Jiaoti Huang

  3. Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA

    Xia Gao

  4. Duke School of Nursing, Duke University, Durham, NC, USA

    Qing Yang

  5. Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, China

    Yue Zhao

  6. Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Daniel George

  7. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA

    Daniel George & Jiaoti Huang

  8. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA

    Yinglu Zhou

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Contributions

LX and JH conceived and designed the study and relevant experiments. LX, BZ, WB, HX, NS, SH, HZ, DM and JH performed experiments, analyzed and interpreted the data. XG performed metabolic profiling and tracing experiments. JG conducted immunuhistochemical staining. QY and YZ performed bioinformatics and statistical analyses. XC and YH assisted animal studies. LX and JH supervised the study, interpreted the data and co-wrote the manuscript. All authors discussed the results, revised and approved the manuscript.

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Correspondence to Jiaoti Huang.

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JH is a consultant for or owns shares in the following companies: Kingmed, MoreHealth, OptraScan, Genetron, Omnitura, Vetonco, York Biotechnology, Genecode, VIVA Biotechnology and Sisu Pharma.

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Xu, L., Zhao, B., Butler, W. et al. Targeting glutamine metabolism network for the treatment of therapy-resistant prostate cancer. Oncogene 41, 1140–1154 (2022). https://doi.org/10.1038/s41388-021-02155-z

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