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 (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.
Chinnakannu
Kannagi
K
Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan, USA.
Chen
Di
D
Li
Yiwei
Y
Wang
Zhiwei
Z
Dou
Q Ping
QP
Reddy
G Prem Veer
GP
Sarkar
Fazlul H
FH
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007532:Isoleucine / Q000378:metabolism; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011944:Receptors, Androgen / Q000378:metabolism
C436291:CDKN1B protein, human; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D061988:Proteasome Inhibitors; D011944:Receptors, Androgen; D007532:Isoleucine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011065:Poly(ADP-ribose) Polymerases; D046988:Proteasome Endopeptidase Complex; C016392:3,3'-diindolylmethane