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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-10, Vol.66 (20), p.10064-10072
• Main Authors: BHUIYAN, Mohammad M. R, YIWEI LI, BANERJEE, Sanjeev, AHMED, Fakhara, ZHIWEI WANG, ALI, Shadan, SARKAR, Fazlul H
• Format: Article
• Language: English
• Subjects: Androgen Receptor Antagonists; Anticarcinogenic Agents - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; Cell Nucleus - metabolism; Down-Regulation - drug effects; Gynecology. Andrology. Obstetrics; Humans; Indoles - pharmacology; Male; Male genital diseases; Medical sciences; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Nephrology. Urinary tract diseases; NF-kappa B - metabolism; Pharmacology. Drug treatments; Prostate-Specific Antigen - antagonists & inhibitors; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Androgen - biosynthesis; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-2011

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.