Prostaglandin 15d-PGJ2 Inhibits Androgen Receptor Signaling in Prostate Cancer Cells

Abstract

Androgen signaling, in particular overexpression of the androgen receptor (AR), is critical for the growth and progression of prostate cancer. Because the AR is amenable to targeting by small-molecule inhibitors, it remains the major druggable target for the advanced disease. Inflammation has also been implicated in the cancerous growth in the prostate. Here we show that 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenously produced antiinflammatory prostaglandin, targets the AR and acts as a potent AR inhibitor, rapidly repressing AR target genes, such as FKBP51 and TMPRSS2 in prostate cancer cells. However, exposure of prostate cancer cells to 15d-PGJ(2) does not simply evoke a general inhibition of nuclear receptor activity or transcription because under the same conditions, peroxisome proliferator-activated receptor-γ is activated by 15d-PGJ(2). Moreover, 15d-PGJ(2) rapidly triggers modifications of AR by small ubiquitin-related modifier-2/3 (SUMO-2/3), which may modulate the repressing effect of 15d-PGJ(2) on AR-dependent transcription. Chromatin immunoprecipitation assays indicate that the inhibitory effect of 15d-PGJ(2) on FKBP51 and TMPRSS2 expression occurs in parallel with the inhibition of the AR binding to the regulatory regions of these genes. However, the DNA-binding activity is not the only AR function targeted by 15d-PGJ(2) because the prostaglandin also blunted the androgen-dependent interaction between the AR amino and carboxy termini. In conclusion, our results identify 15d-PGJ(2) as a potent and direct inhibitor of androgen signaling, suggesting novel possibilities in restricting the AR activity in prostate cancer cells.