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Edited by Karen H. Vousden, Francis Crick Institute, London, United Kingdom, and approved February 24, 2021 (received for review June 19, 2020)
Significance
We report that androgen receptor (AR) promotes glutaminase 1 (GLS1) expression and glutamine utilization to support the survival of prostate cancer (PCa) cells. Hormonal therapy inhibits AR and decreases GLS1 expression and glutamine utilization to achieve therapeutic effect. Our results suggest that eventually the tumor cells switch GLS1 expression from the AR-dependent KGA isoform to the androgen-independent and enzymatically more potent GAC isoform, which increases glutamine utilization and can contribute to the development of castration-resistant PCa. Our work has discovered a previously unknown AR function, a metabolic mechanism of hormonal therapy and an important therapeutic target more specific than AR. Targeting GLS1 may achieve similar therapeutic efficacy but without the side effects resulting from inhibiting AR’s other important physiologic functions.
Abstract
Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.
Footnotes
↵1Present address: Department of Pathology, Anhui Medical University, Hefei, China 230001.
↵2Present address: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China 230001.
- ↵3To whom correspondence may be addressed. Email: huhl{at}sustech.edu.cn or jiaoti.huang{at}duke.edu.
Author contributions: L.X., X.D., H.H., and J.H. designed research; L.X., Y.Y., Y.L., X.C., Y.C., Hong Zhang, J.L., J.B., P.M., Haoyue Zhang, S.Y., J.G., J.W.L., X.G., D.G.T., H.H., and J.H. performed research; L.X. contributed new reagents/analytic tools; L.X., Y.L., X.C., Q.W., X.D., Y.H., D.G., H.H., and J.H. analyzed data; and L.X., H.H., and J.H. wrote the paper.
Competing interest statement: J.H. is a consultant for or owns shares in the following companies: Kingmed, MoreHealth, OptraScan, Genetron, Omnitura, Vetonco, York Biotechnology, Genecode, and Sisu Pharma.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2012748118/-/DCSupplemental.
Data availability
All study data are included in the article and/or supporting information.
Published under the PNAS license.
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A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer
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