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Two independent mechanisms for escaping epidermal growth factor-mediated growth inhibition in epidermal growth factor

M Hirai1, S Gamou, S Minoshima

  • 1Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.

The Journal of Cell Biology
|August 1, 1988
PubMed

Insights

Human squamous cell carcinoma cells with high epidermal growth factor (EGF) receptor levels can escape growth inhibition. Two mechanisms were identified: loss of amplified EGF receptor genes or efficient receptor down-regulation.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Squamous cell carcinoma cell lines frequently exhibit elevated epidermal growth factor (EGF) receptor levels.
  • High EGF receptor expression typically leads to EGF-mediated growth inhibition.

Purpose of the Study:

  • To investigate the mechanisms by which cancer cells with high EGF receptor numbers evade EGF-induced growth inhibition.
  • To identify variants of squamous cell carcinoma lines with altered responses to EGF.

Main Methods:

  • Isolation and characterization of EGF-responsive variants from NA and Ca9-22 cell lines.
  • Scatchard plot analysis for EGF receptor levels.
  • Southern blot and RNA dot blot for EGFR gene copy number.
  • Flow cytometry for ploidy and cell volume.
  • Analysis of EGF receptor autophosphorylation and down-regulation.

Main Results:

  • EGF-dependent growth variants (ER variants) from NA cells showed decreased EGF receptors and loss of amplified EGFR genes.
  • A Ca9-22 variant (CER-1) exhibited EGF-independent growth with increased EGF receptors but similar EGFR gene copy number.
  • CER-1 cells displayed increased ploidy and cell volume, and highly efficient EGF receptor down-regulation.
  • EGF receptor tyrosine kinase activity was similar in parental and variant cells, suggesting no major alteration.

Conclusions:

  • Two distinct mechanisms allow EGF receptor-hyperproducing cells to escape EGF-mediated growth inhibition.
  • A common mechanism involves the loss of amplified epidermal growth factor receptor (EGFR) genes.
  • A novel mechanism involves the efficient down-regulation of cell-surface EGF receptors.

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