Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-induced apoptosis by induction of p21waf1/cip1

Abstract

Background/Aims: We investigated the effect of the peroxisome proliferator-activated receptor-γ(PPAR-γ) agonist pioglitazone on growth and TRAIL-induced apoptosis in carcinoid cells. Methods: Carcinoid cells were incubated without and with pioglitazone. Effects on growth were examined by cell count and cell cycle analysis. p21waf1/cip1 expression was determined by Western blotting. Cytotoxicity assay was performed by FACS analysis. Results: Pioglitazone suppressed the growth and induced apoptosis of carcinoid cells. Additionally, pioglitazone significantly enhanced carcinoid cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The enhancement of TRAIL-induced apoptosis was associated with an upregulation of cyclin-dependent kinase inhibitor p21waf1/cip1 in pioglitazone-treated carcinoid cells. Importantly, overexpression of p21waf1/cip1 in carcinoid cells by adenoviral gene transfer of p21 sensitized them to TRAIL-induced apoptosis. Conclusions: These results suggest that pioglitazone inhibits cell growth and sensitizes cells to TRAIL-induced apoptosis by induction of p21waf1/cip1. Therefore, pioglitazone can be an effective therapeutic adjuvant for the treatment of carcinoid tumors. Copyright © 2001 S. Karger AG, Basel.