ArticleProceedings of the National Academy of Sciences of the United States of America2021
A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59 citing papers in PubMed, 71 citations in OpenAlex.
- Decoding the metabolic‑immune crosstalk: The role of glutamine and ammonium reprogramming in prostate cancer immune evasion (Review).Oncology reports · 2026Review
- RNA therapeutics: current status and future directions.Signal transduction and targeted therapy · 2026Review
- GLS1 Orchestrates Exosome-Mediated Tumor-Endothelial Communication to Facilitate Angiogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.Cell death & disease · 2026Article
- Ferroptosis vulnerability of enzalutamide resistant prostate cancer conferred by ACSL4 overexpression and GPX4 antagonism.Cell death & disease · 2026Article
- Regulation of gene expression by alternative polyadenylation in health and disease.Nature reviews. Genetics · 2026Review
- Integration of a glutamine metabolism-based prognostic signature and a synergistic nanotherapeutic strategy targeting metabolic vulnerabilities in prostate cancer.Discover oncology · 2026Article
- Targeting cancer signaling pathways and their therapeutic strategies.Discover oncology · 2026Review
- A pancancer analysis reveals the oncogenic role of glutaminase 1 (GLS1) in tumor metabolism and immune evasion: a bioinformatics analysis.Discover oncology · 2025Article
- Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.Asian Pacific journal of cancer prevention : APJCP · 2025Review
- AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.Cell discovery · 2025Article
- Imaging the uptake and metabolism of glutamine in prostate tumor models using CEST MRI.Npj imaging · 2025Article
- Targeting Prostate Cancer Metabolism Through Transcriptional and Epigenetic Modulation: A Multi-Target Approach to Therapeutic Innovation.International journal of molecular sciences · 2025Review
- Raman micro-spectroscopy reveals the metabolic alterations in primary prostate tumor tissues of patients with metastases.Journal of translational medicine · 2025Article
- DHA suppresses hormone-sensitive and castration-resistant prostate cancer growth by decreasing de novo lipogenesis.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- Role of multi‑omics in advancing the understanding and treatment of prostate cancer (Review).Molecular medicine reports · 2025Review
- Resilience and vulnerabilities of tumor cells under purine shortage stress.bioRxiv : the preprint server for biology · 2025Article
- Cellular Signaling of Amino Acid Metabolism in Prostate Cancer.International journal of molecular sciences · 2025Review
- Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.Frontiers in oncology · 2025Review
Corrections and comments
- Commented on byUro-Science.2021
Authors and funding
21 authors at 4 institutions in 3 countries.
Funding
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.
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