Related Experiment Video
Updated: Nov 11, 2025
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer
Lingfan Xu1, Yu Yin1, Yanjing Li1
1Department of Pathology, Duke University School of Medicine, Durham, NC 27710.
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.
Insights
Prostate cancer cells alter glutaminase enzyme expression to resist hormone therapy. This switch from kidney-type glutaminase (KGA) to glutaminase C (GAC) drives tumor growth and progression, highlighting a new therapeutic target.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Cancer cells exhibit altered metabolism to fuel uncontrolled growth.
- Mechanisms linking metabolic changes to prostate cancer (PCa) hormonal therapy resistance are not fully understood.
Purpose of the Study:
- To investigate the role of glutaminase isoforms in PCa hormonal therapy resistance and disease progression.
- To elucidate the mechanism of glutaminase isoform switching under androgen deprivation.
Main Methods:
- Analysis of glutaminase 1 (GLS1) splicing isoforms (KGA and GAC) in PCa.
- Investigating the regulation of GLS1 isoforms by androgen receptor (AR).
- Evaluating the therapeutic efficacy of targeting GAC in vitro and in vivo models of PCa.
Main Results:
- Androgen deprivation therapy initially suppresses kidney-type glutaminase (KGA) expression, mediated by AR.
- Tumor cells adapt by switching to androgen-independent glutaminase C (GAC), enhancing glutaminolysis and proliferation.
- Targeting GAC demonstrated superior efficacy in castration-resistant PCa models compared to hormone-sensitive models.
Conclusions:
- A glutaminase isoform switch mechanism is identified as a key driver of PCa therapeutic resistance and progression.
- Androgen receptor signaling influences cancer metabolism through regulation of GLS1 isoforms.
- Glutaminase C (GAC) represents a potential therapeutic target for advanced prostate cancer.
