title: 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.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Shihua
authors.initials: S
authors.lastname: Wang
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Janel
authors.initials: J
authors.lastname: Suburu
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Gu
authors.forename: Jiaozhong
authors.initials: J
authors.lastname: Cai
authors.forename: Linara S
authors.initials: LS
authors.lastname: Axanova
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Donna L
authors.initials: DL
authors.lastname: Perry
authors.forename: Iris J
authors.initials: IJ
authors.lastname: Edwards
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sinnott
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Loda
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Berquin
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004042:Dietary Fats, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D055785:Gene Knockdown Techniques / Q000379:methods; D055786:Gene Knockout Techniques; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
chemical_list: D004042:Dietary Fats, Unsaturated; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D011944:Receptors, Androgen; D044943:Fatty Acid Desaturases; C078565:omega-3 fatty acid desaturase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D046988:Proteasome Endopeptidase Complex