Cell Cycle-Dependent Effects of 3,3′-Diindolylmethane on Proliferation and Apoptosis of Prostate Cancer Cells

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 (13C) 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-kappa B, 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-kappa B 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.