Id-1-induced Raf/MEK pathway activation is essential for its protective role against taxol-induced apoptosis in nasopharyngeal carcinoma cells

Carcinogenesis. 2004 Jun;25(6):881-7. doi: 10.1093/carcin/bgh087. Epub 2004 Jan 23.

Abstract

Increasingly, evidence supports the function of the helix-loop-helix protein Id-1 (inhibitor of differentiation/DNA binding-1) as an oncogene. Over-expression of Id-1 is not only observed in many types of human cancer but its expression levels have been correlated with cancer progression. However, little is known about the molecular mechanisms responsible for the function of Id-1. Recently, we and others reported that Id-1-induced cell proliferation was mediated through a Raf/MEK signalling pathway. In this study, we investigated if ectopic Id-1 expression in nasopharyngeal carcinoma cells had any protective effect on taxol-induced death, which is also regulated through Raf/MEK pathway. Using four stable Id-1 transfectant clones, we found that exogenous Id-1 expression led to phosphorylation of Raf-1 and MEK1/2 kinases, which was associated with resistance to taxol. Treatment of the Id-1 expressing cells with a MEK inhibitor, PD098059, resulted in an increased taxol-induced apoptosis rate in Id-1 transfectants compared with the vector control. In addition, the fact that the taxol-induced apoptosis rate, down-regulation of Bcl-2 and up-regulation of Bax were suppressed by PD098059 treatment in Id-1 expressing cells indicates that the Id-1 induced cellular protection against apoptosis is mediated through Raf/MEK signalling pathways. Our results suggest that Id-1 may be an upstream regulator of the Raf/MEK signalling pathway, which plays an essential role in protection against taxol-induced apoptosis. Our evidence also indicates a novel treatment strategy to increase anticancer drug-induced apoptosis through inactivation of the Id-1 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Line, Tumor
  • Enzyme Activation
  • Humans
  • Inhibitor of Differentiation Protein 1
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Kinase Kinases / physiology*
  • Nasopharyngeal Neoplasms / pathology
  • Nasopharyngeal Neoplasms / physiopathology*
  • Paclitaxel / pharmacology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins c-raf / physiology*
  • Repressor Proteins*
  • Signal Transduction*
  • Transcription Factors / physiology*

Substances

  • Antineoplastic Agents, Phytogenic
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • Repressor Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins c-raf
  • MAP Kinase Kinase Kinases
  • Paclitaxel