Induction of heat shock proteins by heregulin beta1 leads to protection from apoptosis and anchorage-independent growth

Oncogene. 2005 Sep 29;24(43):6564-73. doi: 10.1038/sj.onc.1208798.

Abstract

Elevation of heat shock protein (HSP) levels is widespread in cancer and predicts a poor prognosis and resistance to therapy. We show that HSP elevation in tumor cells can be induced by the highly malignant factor heregulin beta1 (HRGbeta1), which induces HSP expression through heat shock transcription factor 1 (HSF1). Inactivation of the hsf1 gene prevents HSP induction by HRGbeta1. HSP expression is induced through a cascade response initiated by HRGbeta1 binding to c-erbB receptors on the cell surface and which leads to the inhibition of intracellular HSF1 antagonist glycogen synthase kinase 3. HSF1 activated by this pathway plays a key role in the protection of cells from apoptosis and the mediation of anchorage independent growth by HRGbeta1, indicating a role for HSF1 in this tumorigenic pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Proliferation
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • Glycogen Synthase Kinase 3 / metabolism
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins / drug effects
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Mice
  • Neuregulin-1 / metabolism*
  • Neuregulin-1 / pharmacology
  • Oncogene Proteins v-erbB / genetics
  • Oncogene Proteins v-erbB / metabolism
  • Signal Transduction
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay

Substances

  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • Neuregulin-1
  • Oncogene Proteins v-erbB
  • Transcription Factors
  • heregulin beta1
  • Glycogen Synthase Kinase 3