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Carcinogenesis Advance Access published online on August 18, 2006
Carcinogenesis, doi:10.1093/carcin/bgl144
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received March 15, 2006
Revised August 4, 2006
Accepted August 9, 2006

CANCER PREVENTION

D,L-Sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1

Sunga Choi 1, Karen L. Lew 1, Hui Xiao 1, Anna Herman-Antosiewicz 1, Dong Xiao 1, Charles K. Brown 2, and Shivendra V. Singh 1 *

1 Department of Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2 Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

* To whom correspondence should be addressed.
Shivendra V. Singh, E-mail: singhs{at}upmc.edu


  Abstract

D,L-Sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived isomer L-SFN, suppresses proliferation of cancer cells by causing apoptosis but the mechanism of cell death is not fully understood. We used LNCaP (wild-type p53) and PC-3 (p53 deficient) human prostate cancer cells to gain further insights into the mechanism of SFN-induced apoptosis. The LNCaP cell line was relatively more sensitive to SFN-induced apoptosis compared with PC-3. The SFN treatment caused stabilization of p53 protein in LNCaP cells, but SFN-mediated apoptosis was not attenuated by knockdown of p53 protein. Instead, the differential sensitivity of these cells to SFN-induced apoptosis correlated with difference in kinetics of Bax conformational change. Ectopic expression of Bcl-2 failed to confer protection against SFN-induced cell death in LNCaP cells. Treatment of PC-3 cells with SFN resulted in a marked decrease in the levels of inhibitor of apoptosis (IAP) family proteins (cIAP1, cIAP2 and XIAP), which was accompanied by inhibition of nuclear translocation of p65-nuclear factor {kappa}B (NF{kappa}B). The effect of SFN on levels of IAP family proteins as well as transcriptional activity of NF{kappa}B was biphasic in LNCaP cells. The SFN treated LNCaP and PC-3 cells exhibited a marked increase in protein level of Apaf-1, which was accompanied by an increase in transcriptional activity of E2F1. The SFN-induced apoptosis in both cell lines was significantly attenuated by Apaf-1 protein knockdown. In conclusion, the present study reveals a complex signaling mechanism involving Bax activation, down-regulation of IAP family proteins and Apaf-1 induction in regulation of SFN-induced cell death.

Keywords: D,L-Sulforaphane; IAP; Apaf-1; Apoptosis; Prostate Cancer; Chemoprevention.
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