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Abstract
Deletion or mutation of the androgen receptor (AR) renders prostate tumors refractory to apoptosis by androgen ablation, the mainstay of prostate cancer therapy. To identify novel therapeutics that can induce apoptosis regardless of the AR status of prostate cancer cells, we screened dietary herbal compounds using a reporter assay for the prostate apoptosis response-4 (Par-4) gene, which induces p53- and PTEN-independent and cancer-selective apoptosis. One of the compounds, withaferin A (WA), a major constituent of the dietary compound Withania somnifera, induced Par-4-dependent apoptosis in androgen-refractory prostate cancer cells and regression of PC-3 xenografts in nude mice. Interestingly, restoration of wild-type AR in PC-3 (AR negative) cells abrogated both Par-4 induction and apoptosis by WA. Individually, WA and anti-androgens induced neither Par-4 nor apoptosis in androgen-responsive prostate cancer cells, yet in combination, WA and anti-androgen synergistically induced Par-4 and apoptosis in androgen-responsive prostate cancer cells. Thus, when judiciously combined with anti-androgens, WA inhibits survival of both androgen-responsive and androgen-refractory prostate cancer cells by a Par-4-dependent mechanism. As Par-4 up-regulation induces apoptosis in most tumor cells, our findings can be extended to high-throughput screens to identify synergistic combinations for both therapy-sensitive and therapy-resistant cancers.
Highlights
Prostate cancer is the third leading cause of cancer-related deaths in men in the United States [1]
As prostate apoptosis response-4 (Par-4) is induced exclusively by apoptotic insults, and not during growth stimulation, growth arrest, or necrosis [14], and the elevation of Par-4 expression induces p53- and PTEN-independent apoptosis of cancer cells and tumor regression [44, 45], we developed a cell-based assay using Par-4 expression as a molecular indicator to screen for natural dietary compounds with apoptotic potential
The transfectants were treated with either vehicle (DMSO) or various natural dietary compounds for 6 h, and induction of the Par-4 promoter was analyzed by luciferase assays
Summary
Prostate cancer is the third leading cause of cancer-related deaths in men in the United States [1]. About 234,460 new cases of prostate cancer are diagnosed annually in the United States alone, and the numbers are projected to increase as longevity expands the aging population [1] Both androgen and its cognate receptor [androgen receptor (AR)] are recognized risk factors in the development of prostate cancer [2,3,4,5]. AR can be activated despite androgen blockade therapy in AR-positive prostate cancer [12] This is attributed to an increased sensitivity of AR to low concentrations of androgen due to mutations in AR, AR partner-protein interactions, or post-translational modifications; these underlying factors function to promote androgen depletion-independent signaling [13]. Alternative therapeutic approaches to inhibit AR function in a ligand-independent manner are needed to treat prostate cancer
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