Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a memb er of the nuclear receptor superfamily, Recent studies found that Ligand-ac tivated PPAR gamma regulated differentiation and clonal growth of several t ypes of cancer cells, including prostate cancer, suggesting that PPAR gamma could be a tumor suppressor. Troglitazone was a widely used antidiabetic d rug that activates RPAR gamma. Recently, we reported that this agent had an tiprostate cancer effects in vitro and in vivo. In this study, we administe red troglitazone for over 1.5 years to an individual with occult recurrent prostate cancer. Using the prostate-specific antigen (PSA) levels as a surr ogate marker of the disease, the oral administration of troglitazone (600-8 00 mg/day) reduced the increase velocity of PSA levels, suggesting clinical efficacy of troglitazone in prostate cancer. PSA promoter/enhancer reporte r assays showed that the PPAR gamma ligands troglitazone (10(-5) M), piogli tazone (10(-5) M), or 15-deoxy-Delta 12,14-prostaglandin J(2) (10-5 M) down -regulated androgen-stimulated reporter gene activity in LNCaP cells, a pro state cancer cell line, The PSA promoter contains androgen receptor respons e elements (AREs), Reporter gene studies showed that troglitazone inhibited androgen activation of the AREs in the PSA regulatory region. Consistent w ith inhibition of gene expression, 2 days of incubation of LNCaP with trogl itazone dramatically suppressed PSA protein expression without suppressing AR expression, suggesting that troglitazone inhibited ARE activation by a m echanism other than down-regulation of expression of the AR. Taken together , ligands of PPAR gamma may be a useful therapeutic approach for the treatm ent of prostate cancer and may be acting, in part, by inhibiting transactiv ation of androgen-responsive genes.