Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells.
Despite the initial efficacy of androgen deprivation therapy, most patients with advanced prostate cancer eventually progress to hormone-refractory prostate cancer, for which there is no curative therapy. Previous studies from our laboratory and others have shown the antiproliferative and proapoptotic effects of 3,3'-diindolylmethane (DIM) in prostate cancer cells. However, the molecular mechanism of action of DIM has not been investigated in androgen receptor (AR)-positive hormone-responsive and -nonresponsive prostate cancer cells. Therefore, we investigated the effects of B-DIM, a formulated DIM with greater bioavailability, on AR, Akt, and nuclear factor kappaB (NF-kappaB) signaling in hormone-sensitive LNCaP (AR+) and hormone-insensitive C4-2B (AR+) prostate cancer cells. We found that B-DIM significantly inhibited cell proliferation and induced apoptosis in both cell lines. By Akt gene transfection, reverse transcription-PCR, Western blot analysis, and electrophoretic mobility shift assay, we found a potential crosstalk between Akt, NF-kappaB, and AR. Importantly, B-DIM significantly inhibited Akt activation, NF-kappaB DNA binding activity, AR phosphorylation, and the expressions of AR and prostate-specific antigen, suggesting that B-DIM could interrupt the crosstalk. Confocal studies revealed that B-DIM inhibited AR nuclear translocation, leading to the down-regulation of AR target genes. Moreover, B-DIM significantly inhibited C4-2B cell growth in a severe combined immunodeficiency-human model of experimental prostate cancer bone metastasis. These results suggest that B-DIM-induced cell proliferation inhibition and apoptosis induction are partly mediated through the down-regulation of AR, Akt, and NF-kappaB signaling. These observations provide a rationale for devising novel therapeutic approaches for the treatment of hormone-sensitive, but more importantly, hormone-refractory prostate cancer by using B-DIM alone or in combination with other therapeutics.
Bhuiyan
Mohammad M R
MM
Departments of Pathology and Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Li
Yiwei
Y
Banerjee
Sanjeev
S
Ahmed
Fakhara
F
Wang
Zhiwei
Z
Ali
Shadan
S
Sarkar
Fazlul H
FH
D059002:Androgen Receptor Antagonists; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D059002:Androgen Receptor Antagonists; D016588:Anticarcinogenic Agents; D007211:Indoles; D016328:NF-kappa B; D011944:Receptors, Androgen; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen; C016392:3,3'-diindolylmethane