1. ¹Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Pulmonology, AP-HP, Hopital Tenon, Paris, France
3. ³Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5. ⁵Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6. ⁶Hamon Center for Therapeutic Oncology Research, University of Texas-Southwestern Medical Center, Dallas, TX, USA
7. ⁷Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

Correspondence: Dr JM Kurie, Department of Thoracic/Head and Neck Medical Oncology, Box 0432, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. E-mail: jkurie@mdanderson.org

Received 28 July 2006; Revised 31 August 2006; Accepted 1 September 2006; Published online 23 October 2006.

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.