Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

J. Brognard, P. A. Dennis

Research output: Contribution to journalArticle

Abstract

To evaluate the role of the MEK/ERK pathway in NSCLC survival, we analyzed NSCLC cell lines that differed in tumor histology and status of p53, Rb, and K-ras. Constitutive ERK1/2 activity was demonstrated in 17 of 19 cell lines by maintenance of ERK1/2 phosphorylation with serum deprivation. Phosphorylation of ERK1/2 correlated with phosphorylation of MEK1/2 and p90RSK, but was inversely correlated with phosphorylation of c-Raf at S259. With serum deprivation, the MEK inhibitors, PD98059 and U0126, inhibited ERK1/2 activity but did not increase apoptosis. PD98059 and U0126 induced cell cycle arrest in Go/Gi in cells with the highest levels of ERK1/2 activity, which correlated with induction of p27 but not p21. To confirm the cytostatic response to MEK inhibitors, we performed transient transfections with dominant negative forms of MEK or ERK. Surprisingly, dominant negative MEK and ERK mutants increased apoptosis without affecting cell cycle or p27 levels. When combined with paclitaxel, MEK inhibitors had no effect on apoptosis. In contrast, dominant negative ERK2 potentiated paclitaxel-induced apoptosis. Our studies show that constitutive ERK1/2 activity in NSCLC cells promotes cellular survival and chemotherapeutic resistance. Moreover, our data are the first to demonstrate divergent cellular responses to inhibition of the MEK/ERK pathway by small molecule inhibitors or dominant negative mutants.

Original languageEnglish (US)
Pages (from-to)893-904
Number of pages12
JournalCell Death and Differentiation
Volume9
Issue number9
DOIs
StatePublished - Sep 2002
Externally publishedYes

Fingerprint

MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Phosphorylation
Apoptosis
Paclitaxel
Cell Line
Cytostatic Agents
Cell Cycle Checkpoints
Serum
Transfection
Histology
Cell Cycle
Maintenance
Neoplasms
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
U 0126

Keywords

  • Apoptosis
  • Chemotherapy
  • ERK
  • Kinase
  • Lung cancer

ASJC Scopus subject areas

  • Cell Biology

Cite this

Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants. / Brognard, J.; Dennis, P. A.

In: Cell Death and Differentiation, Vol. 9, No. 9, 09.2002, p. 893-904.

Research output: Contribution to journalArticle

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