Effects of ligand activation of peroxisome proliferator-activated receptorgamma in human prostate cancer

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes . Activation of this receptor in liposarcomas and breast and colon cancer c ells also induces cell growth inhibition and differentiation. In the presen t study, we show that PPAR gamma is expressed in human prostate adenocarcin omas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPAR gamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our pre clinical data, we conducted a phase II clinical study in patients with adva nced prostate cancer using troglitazone, a PPAR gamma ligand used for the t reatment of type 2 diabetes. Forty-one men with histologically confirmed pr ostate cancer and no symptomatic metastatic disease were treated orally wit h troglitazone. An unexpectedly high incidence of prolonged stabilization o f prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specifi c antigen to nearly undetectable levels. These data suggest that PPAR gamma may serve as a biological modifier in human prostate cancer and its therap eutic potential in this disease should be further investigated.