PNAS: SUSTech Hu Hailiang team and others reveal the metabolic mechanism of prostate cancer progression and treatment resistance

Recently, the research group of Associate Professor Hu Hailiang from the School of Medicine of Southern University of Science and Technology and the research group of Professor Huang Jiaoti from the Department of Pathology, Duke University School of Medicine, published a titled: A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate Cancer research paper.

The study thoroughly explored the reasons for the failure of prostate cancer hormone therapy and the development of resistance, and revealed the molecular mechanism by which glutamine metabolism can drive the progression of prostate cancer and produce treatment resistance.

It is expected to provide a new metabolic target for the diagnosis and treatment of prostate cancer, which has important theoretical and translational medicine value and broad prospects for the development and application of biomedicine.

The metabolic reorganization of tumor cells is accompanied by tumor growth, proliferation and migration.

However, how metabolic changes promote hormone therapy resistance and disease progression in prostate cancer remains unclear.

The research team discovered a conversion mechanism of glutamine isoenzymes during hormone therapy of prostate cancer.
This mechanism explains the phenomenon that hormone therapy had the initial therapeutic effect on prostate cancer from the perspective of metabolism, but ultimately failed.

Specifically, Androgen Deprivation Therapy (Androgen Deprivation Therapy) is the standard treatment for hormone-dependent prostate cancer.
It can remove male hormones, thereby preventing the growth of prostate cancer cells and tumors.

The study found that androgen deprivation therapy can inhibit the expression of KGA (kidney-type glutaminase, KGA), a splicing isoenzyme of glutaminase 1 (GLS1), which is regulated by androgen receptor (AR).

Androgen deprivation therapy inhibits the use of glutamine by inhibiting the expression of AR and KGA, so that prostate cancer cells enter a dormant state, thus achieving a therapeutic effect.

However, dormant prostate cancer cells have been latent for a period of time or have some genetic mutations, such as the amplification of the oncogene MYC, resulting in the deprivation of androgens, the tumor cells will express another isoenzyme of GLS1, glutaminase C (GAC), a subtype of GLS1 that has nothing to do with androgens.

The isoenzyme GAC has stronger enzymatic activity and can more effectively use glutamine metabolism to promote the recurrence of prostate cancer cells and transform them into castration-resistant prostate cancer (CRPC).

The study also tested the therapeutic effect of a class of glutaminase inhibitors on prostate cancer, and found that the glutaminase inhibitor CB-839 has better therapeutic effects on castration-resistant prostate cancer in vivo and in vitro than it is sensitive to hormones.
The therapeutic effect of sexual prostate cancer provides a new idea for the treatment of castration-resistant prostate cancer (CRPC), which is to target the glutamine metabolism of the tumor.

Figure: The working model of this study.
In general, the study reported a new molecular metabolic mechanism of prostate cancer resistance to hormone therapy, which has a huge promotion effect on the diagnosis and treatment of prostate cancer.

Hailiang Hu and Jiaoti Huang are the co-corresponding authors of the paper.
Daniel George and Jason Locasale of Duke University, Xu Sheng Dong of the University of British Columbia, and Dean G.
Tang of Roswell Park Cancer Center have made important contributions to the research.

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