Troglitazone activates p21Cip/WAF1 through the ERK pathway in HCT15 human colorectal cancer cells

Cancer Lett. 2002 May 28;179(2):185-95. doi: 10.1016/s0304-3835(01)00869-2.

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 microM of TRO transiently increased extracellular signal regulated kinase (ERK) activity within 15 min, and this subsequently induced p21Cip/WAF1 cell cycle regulator and localized in the nucleus. Raf-1 modification and MEK activation also occurred after TRO treatment, and Elk-1-dependent trans-reporter gene expression was concomitantly induced. The induction and nuclear localization of p21Cip/WAF1 by TRO were blocked by PD98059 pre-treatment, which suggested a role for the ERK pathway in p21Cip/WAF1 activation. TRO inhibited BrdU incorporation and no BrdU incorporation was observed in most p21Cip/WAF1-activated cells. Therefore, TRO regulates the proliferation of HCT15 cells at least partly by a mechanism involving the activation of p21Cip/WAF1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Bromodeoxyuridine / metabolism
  • Cell Division / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Chromans / pharmacology*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / drug effects*
  • Cyclins / metabolism
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • HT29 Cells / drug effects
  • HT29 Cells / metabolism
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Time Factors
  • Transcription Factors*
  • Troglitazone
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • ets-Domain Protein Elk-1

Substances

  • CDKN1A protein, human
  • Chromans
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Enzyme Inhibitors
  • Flavonoids
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Luciferases
  • Mitogen-Activated Protein Kinases
  • Bromodeoxyuridine
  • Troglitazone
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one