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Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer.

ABSTRACT: A common treatment of advanced prostate cancer involves the deprivation of androgens. Despite the initial response to hormonal therapy, eventually all the patients relapse. In the present study, we sought to determine whether dietary polyunsaturated fatty acid (PUFA) affects the development of castration-resistant prostate cancer. Cell culture, patient tissue microarray, allograft, xenograft, prostate-specific Pten knockout and omega-3 desaturase transgenic mouse models in conjunction with dietary manipulation, gene knockdown and knockout approaches were used to determine the effect of dietary PUFA on castration-resistant Pten-null prostate cancer. We found that deletion of Pten increased androgen receptor (AR) expression and Pten-null prostate cells were castration resistant. Omega-3 PUFA slowed down the growth of castration-resistant tumors as compared with omega-6 PUFA. Omega-3 PUFA decreased AR protein to a similar extent in tumor cell cytosolic and nuclear fractions but had no effect on AR messenger RNA level. Omega-3 PUFA treatment appeared to accelerate AR protein degradation, which could be blocked by proteasome inhibitor MG132. Knockdown of AR significantly slowed down prostate cancer cell proliferation in the absence of androgens. Our data suggest that omega-3 PUFA inhibits castration-resistant prostate cancer in part by accelerating proteasome-dependent degradation of the AR protein. Dietary omega-3 PUFA supplementation in conjunction with androgen ablation may significantly delay the development of castration-resistant prostate cancer in patients compared with androgen ablation alone.

SUBMITTER: Wang S

PROVIDER: S-EPMC3271270 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer.

Wang Shihua S Wu Jiansheng J Suburu Janel J Gu Zhennan Z Cai Jiaozhong J Axanova Linara S LS Cramer Scott D SD Thomas Michael J MJ Perry Donna L DL Edwards Iris J IJ Mucci Lorelei A LA Sinnott Jennifer A JA Loda Massimo F MF Sui Guangchao G Berquin Isabelle M IM Chen Yong Q YQ

Carcinogenesis 20111208 2

A common treatment of advanced prostate cancer involves the deprivation of androgens. Despite the initial response to hormonal therapy, eventually all the patients relapse. In the present study, we sought to determine whether dietary polyunsaturated fatty acid (PUFA) affects the development of castration-resistant prostate cancer. Cell culture, patient tissue microarray, allograft, xenograft, prostate-specific Pten knockout and omega-3 desaturase transgenic mouse models in conjunction with dieta ...[more]

PMID: 22159221

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Project description:BackgroundM2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages.MethodsMycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm2. To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay.ResultsThe ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm3) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3).ConclusionsDietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC.

Dataset Information

Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer.

Publications

Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer.

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