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Updated: Jan 12, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Exploiting AR-Synergistic Metabolic Vulnerabilities in Prostate Cancer
Jonathan M Anzules1, Mark Sayegh1,2, Yun Rose Li1,3,4
1Department of Radiation Oncology, City of Hope National Cancer Center, Duarte, California.
Abstract:
Resistance to androgen deprivation therapy remains a major clinical challenge in prostate cancer, necessitating alternative therapeutic strategies. The androgen receptor (AR) plays a central role in driving resistance through mechanisms including enhanced AR signaling, DNA repair, and autophagy. In this issue of Cancer Research, Cordova and colleagues identify a metabolic vulnerability in AR protein synthesis, showing that alternate-day fasting (ADF) impairs AR translation by inducing ribosome collisions on AR mRNA. This stress response activates kinases such as p38 MAPK and selectively reduces AR protein levels, independent of transcription or protein stability. Notably, ADF enhances the efficacy of enzalutamide across multiple prostate cancer models. Unlike conventional AR-targeting approaches, ADF reveals a posttranscriptional dependency of AR expression under nutrient stress while sparing most other proteins. These findings highlight a novel translational vulnerability in prostate cancer and support combining dietary interventions with AR-targeted therapies to overcome resistance and improve patient outcomes. See related article by Cordova et al., p. 4182.
Insights
Alternate-day fasting (ADF) impairs androgen receptor (AR) protein synthesis by inducing ribosome collisions on AR mRNA. This metabolic stress selectively reduces AR levels, enhancing prostate cancer treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Androgen deprivation therapy (ADT) resistance is a major challenge in prostate cancer.
- The androgen receptor (AR) drives resistance through signaling, DNA repair, and autophagy.
- Novel therapeutic strategies are needed to overcome ADT resistance.
Purpose of the Study:
- To identify metabolic vulnerabilities in AR protein synthesis.
- To investigate the effect of alternate-day fasting (ADF) on AR translation.
- To evaluate ADF as a strategy to overcome ADT resistance.
Main Methods:
- Induction of ribosome collisions on AR mRNA via ADF.
- Activation of p38 MAPK stress response.
- Assessment of AR protein levels independent of transcription or stability.
- Evaluation of ADF combined with enzalutamide in prostate cancer models.
Main Results:
- ADF impairs AR translation by inducing ribosome collisions on AR mRNA.
- This stress response selectively reduces AR protein levels.
- ADF enhances enzalutamide efficacy in prostate cancer models.
- ADF targets a posttranscriptional dependency of AR expression.
Conclusions:
- ADF reveals a novel translational vulnerability in AR synthesis.
- Combining dietary interventions with AR-targeted therapies may overcome resistance.
- This approach offers a new strategy to improve prostate cancer patient outcomes.
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