Abstract #11: Transcriptional repression of androgen-receptor by cancer chemopreventive D,L-sulforaphane in human prostate cancer cells

Abstract

Because prostate cancer continues to be a leading cause of cancer related deaths among men in the United States novel strategies for prevention and treatment of this deadly malignancy are highly desirable. We have shown previously that D,L-sulforaphane (SFN), a synthetic analogue of cruciferous-vegetable derived L-isomer, inhibits growth of cultured human prostate cancer cells regardless of their androgen responsiveness or p53 status. We also found that oral gavage of SFN retards growth of PC-3 human prostate cancer xenografts in athymic mice and prostate cancer progression and pulmonary metastasis in a transgenic mouse model of prostate cancer without causing any harmful side effects. We now demonstrate that SFN treatment causes transcriptional repression of androgen receptor (AR), a ligand-activated transcription factor implicated in normal prostate growth and maintenance and prostate cancer development, in cultured human prostate cancer cells. The SFN treatment decreased protein levels of AR in a concentration- and time-dependent manner in LNCaP (an androgen-dependent cell line) and C4-2 (an androgen-independent variant of LNCaP cells) human prostate cancer cell lines. The SFN-mediated suppression of AR protein level was accompanied by significant decrease in cellular as well as secreted levels of prostate specific antigen, an AR-regulated gene product, in both LNCaP and C4-2 cells. RT-PCR analysis revealed dose-dependent decrease in AR mRNA levels indicating transcriptional repression of AR expression by SFN exposure. The SFN treatment also caused significant decrease in AR promoter activity as judged by luciferase reporter assay. Finally, growth of LNCaP and C4-2 cell stimulated by synthetic androgen R1881 was significantly inhibited in the presence of SFN. In conclusion, the present study demonstrates that SFN treatment causes transcriptional suppression of AR leading to down-regulation of PSA protein levels in human prostate cancer cells. This investigation was supported by the USPHS grants CA115498 and CA101753 awarded by the National Cancer Institute.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 11.