Cell cycle-dependent effects of 3,3'-diindolylmethane on proliferation and apoptosis of prostate cancer cells.

Abstract

Epidemiological studies have shown that a diet rich in fruits and cruciferous vegetables is associated with a lower risk of prostate cancer. Indole-3-carbinol (I3C) and its dimeric product 3,3'-diindolylmethane (DIM) have been shown to exhibit anti-tumor activity both in vitro and in vivo. Recently, we have reported that a formulated DIM (B-DIM) induced apoptosis and inhibited growth, angiogenesis, and invasion of prostate cancer cells by regulating Akt, NF-kappaB, VEGF and the androgen receptor (AR) signaling pathway. However, the precise molecular mechanism(s) by which B-DIM inhibits prostate cancer cell growth and induces apoptosis have not been fully elucidated. Most importantly, it is not known how B-DIM affects cell cycle regulators and proteasome activity, which are critically involved in cell growth and apoptosis. In this study, we investigated the effects of B-DIM on proteasome activity and AR transactivation with respect to B-DIM-mediated cell cycle regulation and induction of apoptosis in both androgen-sensitive LNCaP and androgen-insensitive C4-2B prostate cancer cells. We believe that our results show for the first time the cell cycle-dependent effects of B-DIM on proliferation and apoptosis of synchronized prostate cancer cells progressing from G(1) to S phase. B-DIM inhibited this progression by induction of p27(Kip1) and down-regulation of AR. We also show for the first time that B-DIM inhibits proteasome activity in S phase, leading to the inactivation of NF-kappaB signaling and induction of apoptosis in LNCaP and C4-2B cells. These results suggest that B-DIM could be a potent agent for the prevention and/or treatment of both hormone sensitive as well as hormone-refractory prostate cancer.

• Authors: Kannagi Chinnakannu, Di Chen, Yiwei Li, Zhiwei Wang, Q Ping Dou, G Prem Veer Reddy, Fazlul H Sarkar
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 219 Issue 1 Pg. 94-9 (Apr 2009) ISSN: 1097-4652 [Electronic] United States
• PMID: 19062173 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• CDKN1B protein, human
• Indoles
• Intracellular Signaling Peptides and Proteins
• Proteasome Inhibitors
• Receptors, Androgen
• Isoleucine
• Cyclin-Dependent Kinase Inhibitor p27
• Poly(ADP-ribose) Polymerases
• Proteasome Endopeptidase Complex
• 3,3'-diindolylmethane

Topics

• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p27
• Humans
• Indoles (pharmacology)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Isoleucine (metabolism)
• Male
• Poly(ADP-ribose) Polymerases (metabolism)
• Prostatic Neoplasms (metabolism, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• Receptors, Androgen (metabolism)