Activation of the AKT and STAT3 pathways and prolonged survival by a mutant EGFR in human lung cancer cells

Hakan Akca, Masachika Tani, Tomoyuki Hishida, Shingo Matsumoto, Jun Yokota

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

To clarify the pathogenic and biological significance of EGFR mutations in lung cancer, we compared the status of ERBB family receptors, their downstream signal transductions and biological phenotypes between lung cancer cell lines with mutant and wild type EGFR. We initially analyzed expression and phosphorylation of ERBB family receptors and their major downstream proteins, AKT, p44/42 MAPK and STAT3, in a series of lung cancer cell lines with or without EGFR mutation. The expression levels of EGFR as well as of ERBB2 and ERBB3 proteins in cells with EGFR mutation tended to be higher than those in cells with wild type EGFR. There was no difference in stability between mutant and wild type EGFR proteins. EGF induced phosphorylation of EGFR, AKT, p44/42 MAPK and STAT3 to various extents, but the level of induction was not associated with the existence of EGFR mutation. These results implied that the activation of AKT, p44/42 MAPK and STAT3 signaling transmitted by EGFR would be critical for the growth and survival of lung cancer cells, but specific features of mutant EGFR in lung cancer cells was not discriminated by these approaches. We therefore performed transfection studies using PC-13 cells with no detectable endogenous EGFR expression. Exogenous expression of wild type and mutant EGFR (delE746-A750) in the cells revealed that only in the mutant EGFR transfected cells, EGFR itself as well as AKT and STAT3 were highly phosphorylated after 24 h of serum deprivation. The survival time of mutant EGFR transfected cells was prolonged under serum-free culture conditions, but not under standard culture conditions with 10% serum. These results suggest that cells with a mutant EGFR survive through the activation of the AKT and/or STAT3 pathways, even in low EGF microenvironments. This specific property due to EGFR mutation could be an important step of multistage lung cancer progression.

Original languageEnglish
Pages (from-to)25-33
Number of pages9
JournalLung Cancer
Volume54
Issue number1
DOIs
Publication statusPublished - 2006 Oct
Externally publishedYes

Keywords

  • Akt
  • Egfr
  • Lung cancer
  • Mutation
  • Stat3

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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