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Cell Cycle‐Dependent Effects of 3,3′‐Diindolylmethane on Proliferation and Apoptosis of Prostate Cancer Cells
Author(s) -
Chinnakannu Kannagi,
Chen Di,
Li Yiwei,
Wang Zhiwei,
Dou Q. Ping,
Reddy G. Prem Veer,
Sarkar Fazlul H.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21650
Subject(s) - lncap , prostate cancer , apoptosis , cell cycle , transactivation , cell growth , cancer research , proteasome , protein kinase b , androgen receptor , biology , cancer cell , angiogenesis , chemistry , cancer , microbiology and biotechnology , transcription factor , biochemistry , genetics , gene
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‐κB, 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‐κB 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. J. Cell. Physiol. 219: 94–99, 2009. © 2008 Wiley‐Liss, Inc.