c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells

T. S. Khatlani, M. Wislez, M. Sun, H. Srinivas, K. Iwanaga, L. Ma, A. E. Hanna, D. Liu, L. Girard, Y. H. Kim, J. R. Pollack, J. D. Minna, I. I. Wistuba, J. M. Kurie

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

c-Jun N-terminal kinase (JNK) has been reported to either potentiate or inhibit oncogenesis, depending upon the cellular context, but its role in lung neoplasia is unclear. Here we sought to define the role of JNK in lung neoplasia by examining evidence of JNK phosphorylation in non-small-cell lung cancer (NSCLC) biopsy samples and by using genetic and pharmacologic approaches to modulate JNK expression and activity in cultured cells. Immunohistochemical staining for JNK phosphorylation was detected in 114 (45%) of 252 NSCLC biopsy samples and was predominantly nuclear, providing evidence of JNK activation in a subset of NSCLC cases. Introduction of a doxycycline-inducible, constitutively active, mutant mitogen-activated protein kinase kinase 4 (MKK4) into the human bronchial epithelial cell lines BEAS-2B and HB56B increased the cells' proliferation, migration, invasion and clonogenicity. Depletion of JNK in MKK4 mutant-transformed BEAS-2B cells by introduction of JNK1/2 short hairpin RNA reversed the transformed phenotype, indicating that JNK activation is oncogenic and MKK4 confers neoplastic properties in these cells. The proliferation of NSCLC cell lines HCC827 and H2009, in which JNK and its substrate c-Jun are constitutively phosphorylated, was inhibited by SP600125, a JNK kinase inhibitor. We conclude that JNK is activated in a subset of NSCLC biopsy samples and promotes oncogenesis in the bronchial epithelium, suggesting that strategies to inhibit the JNK pathway should be considered for the prevention and treatment of NSCLC.

Original languageEnglish (US)
Pages (from-to)2658-2666
Number of pages9
JournalOncogene
Volume26
Issue number18
DOIs
StatePublished - Apr 19 2007

Keywords

  • Cellular transformation
  • Lung cancer
  • c-Jun N-terminal kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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