Troglitazone activates p21(Cip/WAF1) through the ERK pathway in HCT15 human colorectal cancer cells

Abstract

In this study, we identified a new mechanism for the anti-proliferation of HCT15 colorectal cancer cells by troglitazone (TRO). Treating HCT15 cells with 20 muM of TRO transiently increased extracellular signal regulated kinase (ERK) activity within 15 min, and this subsequently induced p21(Cip/WAF1) cell cycle regulator and localized in the nucleus. Raf-1 modification and MEK activation also occurred after TRO treatment, and Elk-l-dependent trans-reporter gene expression was concomitantly induced. The induction and nuclear localization of p21(Cip/WAF1) by TRO were blocked by PD98059 pre-treatment, which suggested a role for the ERK pathway in p21(Cip/WAF1) activation. TRO inhibited BrdU incorporation and no BrdU incorporation was observed in most p21(Cip/WAF1)-activated cells. Therefore, TRO regulates the proliferation of HCT15 cells at least partly by a mechanism involving the activation of p21(Cip/WAF1). (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.