Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFkappaB via suppression of GSK-3beta expression.

摘要

PPARgamma ligands have been reported to reduce proliferation of human prostate cancer cells. However, the molecular mechanism of PPARgamma agonist-induced cell growth inhibition of prostate cancer cells is not clear. GSK-3beta expression and NFkappaB activity have important roles in prostate cancer development. To investigate the mechanisms of the PPARgamma agonist-induced prostate cancer cell growth inhibition, we examined the effect of troglitazone on the expression of PPARgamma, GSK-3beta and activity of NFkappaB as well as on the prostate cancer cell growth. Troglitazone induced the expression of PPARgamma in the nuclear of PC-3 cells, but not in LNCaP cells. Troglitazone (0-16 uM) inhibited cancer cell growth in a similar extend between both cells accompanied by the induction of cell cycle arrest in G(0)/G(1) phase and an increased in the similar extent of apoptotic cell death in concentration dependent manner. Troglitazone inhibited the constitutive expression of GSK-3beta and activation of NFkappaB. Co-treatment of troglitazone with a GSK-3beta inhibitor (AR-a014418) or GSK-3beta siRNA significantly augmented the inhibitory effect of troglitazone on the NFkappaB activity and on prostate cancer cell growth inhibition and apoptotic cell death. However, overexpression of GSK-3beta hindered troglitazone-induced cell growth inhibition and NFkappaB inactivation. These results suggest that PPARgamma agonist, troglitazone, inhibits prostate cancer cell growth through inactivation of NFkappaB via suppression of GSK-3beta expression.