PPARγ ligands regulate the invasion of androgen-independent human prostate cancer cells.

B92

Prostate cancer is a disease that affects one-third of the United States male population. African American men have the highest incidence of prostate cancer and are more likely to die from the disease as compared to Caucasian men. To decrease the prostate cancer morbidity rate among African Americans in the United States, more effective treatments for prostate cancer must be identified. Our group and others have shown that ligands for the peroxisome proliferator activated receptor gamma (PPARγ), a part of the nuclear receptor superfamily, inhibit the growth of human androgen-independent prostate cancer cells. PPARγ ligands have also been shown to play a role in the invasion and metastasis of breast, colon, and lung cancers. However, it is not known if PPARγ ligands regulate the processes required for the formation of distant prostate cancer metastases. Therefore, the goal of this study was to investigate the effect of PPARγ ligands on the invasion of the androgen-independent PC-3 and C4-2 human prostate cancer cell lines. Through Boyden chamber invasion assays, we found that growth inhibitory concentrations of PPARγ ligands ciglitazone, troglitazone and rosiglitazone inhibit the invasion of androgen-independent cells through Matrigel. It has been shown that the phosphoinositide 3-kinase (PI3K) pathway, which is involved in the regulation of cell proliferation and tumor cell invasion, is up-regulated in advanced prostate cancer cells. To test the hypothesis that PPARγ ligands inhibit cell invasion by altering the PI3K pathway, we examined the effects of PPARγ ligands on the expression and/or activation of PI3K signaling proteins Akt and p70 S6 kinase. Western blot analysis was used to detect alterations in kinase activation and total kinase levels. In PC-3 cells, ciglitazone, troglitazone and rosiglitazone reduced p70 S6 kinase activation, as measured by a decrease in p70 S6 kinase phosphorylation. However, they did not regulate Akt activation or total Akt protein levels. Another protein, AMP-activated associated kinase (AMPK) has been shown to negatively regulate the PI3K pathway by inhibiting p70 S6 kinase phosphorylation. In PC-3 cells exposed to the PPARγ ligand ciglitazone, there was an increase in AMPK activation prior to the decrease in p70 S6 kinase activation. These data suggest that PPARγ ligands elicit anti-invasion effects in androgen-independent human prostate cancer cells by altering the activation of p70 S6 kinase via AMPK. Supported by U.S. Army Medical Research and Materiel Command Prostate Cancer Research Program New Investigator Award (W81XWH-05-1-0605) and the MMC-VICC U54 Cancer Partnership Grant.