title: 3,3'-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model.
abstract: 3,3'-Diindolylmethane (DIM) is a major in vivo derivative of indole-3-carbinol, which is present in cruciferous vegetables and has been reported to possess anti-carcinogenic properties. In the present study, we examined whether DIM inhibits the development of prostate cancer using the transgenic adenocarcinoma mouse prostate (TRAMP) model. DIM feeding inhibited prostate carcinogenesis in TRAMP mice, reduced the number of cells expressing the SV40 large tumor antigen and proliferating cell nuclear antigen, and increased the number of terminal dUTP nick-end labeling-positive cells in the dorsolateral lobes of the prostate. Additionally, DIM feeding reduced the expression of cyclin A, cyclin-dependent kinase (CDK)2, CDK4, and Bcl-xL, and increased p27 and Bax expression. To assess the mechanisms by which DIM induces apoptosis, LNCaP and DU145 human prostate cancer cells were cultured with various concentrations of DIM. DIM induced a substantial reduction in the numbers of viable cells and induced apoptosis in LNCaP and DU145 cells. DIM increased the cleavage of caspase-9, -7, -3, and poly (ADP-ribose) polymerase (PARP). DIM increased mitochondrial membrane permeability and the translocation of cytochrome c and Smac/Diablo from the mitochondria. Additionally, DIM induced increases in the levels of cleaved caspase-8, truncated Bid, Fas, and Fas ligand, and the caspase-8 inhibitor Z-IETD-FMK was shown to mitigate DIM-induced apoptosis and the cleavage of caspase-3, PARP, and Bid. These results indicate that DIM inhibits prostate carcinogenesis via induction of apoptosis and inhibition of cell cycle progression. DIM induces apoptosis in prostate cancer cells via the mitochondria- and death receptor-mediated pathways.
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Han Jin
authors.initials: HJ
authors.lastname: Cho
authors.forename: So Young
authors.initials: SY
authors.lastname: Park
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.forename: Jin-Kyung
authors.initials: JK
authors.lastname: Kim
authors.forename: Jung Han Yoon
authors.initials: JH
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000032:analysis; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D019925:Cyclin A / Q000032:analysis; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D045304:Cytochromes c / Q000032:analysis; D004195:Disease Models, Animal; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000032:analysis; D009842:Oligopeptides / Q000627:therapeutic use; D010455:Peptides; D010539:Permeability / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D021381:Protein Transport / Q000187:drug effects; D051020:bcl-X Protein / Q000032:analysis
chemical_list: D016588:Anticarcinogenic Agents; D000952:Antigens, Polyomavirus Transforming; D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D019925:Cyclin A; C499605:Diablo protein, mouse; D007211:Indoles; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D010455:Peptides; D018809:Proliferating Cell Nuclear Antigen; D051020:bcl-X Protein; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C065723:poly (arginyl-glycyl-aspartic acid); D050760:Cyclin-Dependent Kinase Inhibitor p27; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D020169:Caspases; C016392:3,3'-diindolylmethane