| Abstract | 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. |
| Authors | Mohammad M R Bhuiyan, Yiwei Li, Sanjeev Banerjee, Fakhara Ahmed, Zhiwei Wang, Shadan Ali, Fazlul H Sarkar
(Affiliation: Departments of Pathology and Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.)
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| Journal | Cancer research
(Cancer Res)
Vol. 66
Issue 20
Pg. 10064-72
(Oct 15 2006)
ISSN: 0008-5472 United States |
| PMID | 17047070
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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| Chemical References |
- Anticarcinogenic Agents
- Indoles
- NF-kappa B
- Receptors, Androgen
- 3,3'-diindolylmethane
- Proto-Oncogene Proteins c-akt
- Prostate-Specific Antigen
|
| Topics |
- Anticarcinogenic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Bone Neoplasms
(drug therapy, pathology)
- Cell Growth Processes
(drug effects)
- Cell Line, Tumor
- Cell Nucleus
(metabolism)
- Down-Regulation
(drug effects)
- Humans
- Indoles
(pharmacology)
- Male
- NF-kappa B
(metabolism)
- Neoplasms, Hormone-Dependent
(drug therapy, metabolism, pathology)
- Prostate-Specific Antigen
(antagonists & inhibitors)
- Prostatic Neoplasms
(drug therapy, metabolism, pathology)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Receptors, Androgen
(antagonists & inhibitors, biosynthesis, metabolism)
- Signal Transduction
(drug effects)
|
