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Caloric restriction enhances the activity of anti-androgen therapy by inhibiting androgen receptor translation in prostate cancer

ABSTRACT: Epidemiological studies suggest that diet can impact the incidence, progression, and response to treatment of multiple cancers, including prostate cancer (PCa). In this study, we investigated the use of dietary interventions, specifically caloric or protein restriction, in combination with anti-androgen therapy as a treatment for PCa. We found that caloric restriction through alternate-day fasting (ADF) reduces androgen receptor (AR) expression and signaling. This reduction in AR enhances the antitumor activity of the AR antagonist enzalutamide in multiple mouse models of PCa. Mechanistic studies reveal that nutrient starvation via ADF predominantly decreases AR mRNA translation at the elongation stage due to amino acid limitation. Pharmacological agents that similarly impair translation elongation and promote ribosome collisions mimic the AR translation reduction observed with ADF. We propose that amino acid limitation through ADF impairs translation elongation in PCa, and AR mRNA translation is susceptible to this process, leading to a reduction in AR protein levels and enhancing AR-targeted therapy. This study suggests that fasting-induced caloric restriction may improve the efficacy of anti-androgen therapy in PCa.

ORGANISM(S): Mus musculus

PROVIDER: GSE261842 | GEO | 2025/02/28

REPOSITORIES: GEO

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Project description:The androgen receptor (AR) plays a key role in progression to incurable androgen-ablation resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand binding domain (designated as AR3, AR4 and AR5) in hormone insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly upregulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells while specific knock-down of AR3 expression (without altering AR level) in hormone resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct yet essential role in ablation-independent growth through regulating a unique set of genes including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation-independence during PCA progression and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available anti-androgen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. Total RNA was extracted from CWR-R1 and 22Rv1 cells treated with shAR3-1, shARa and the scrambled shRNA control, respectively. Each of CWR-R1 and 22Rv1 cells treated with shAR3-1 was compared with the scrambled shRNA control. The same experiments were performed for the cells treated with shARa.

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Caloric restriction enhances the activity of anti-androgen therapy by inhibiting androgen receptor translation in prostate cancer

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