c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells
| Autor: | Luc Girard, Mianen Sun, Jonathan R. Pollack, Harish Srinivas, Diane Liu, Marie Wislez, Amy E. Hanna, Tanvir Khatlani, Kentaro Iwanaga, Ignacio I. Wistuba, John D. Minna, Lijiang Ma, Young Ho Kim, Jonathan M. Kurie |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Lung Neoplasms MAP Kinase Kinase 4 Proto-Oncogene Proteins c-jun Bronchi Biology medicine.disease_cause Small hairpin RNA Cell Movement Carcinoma Non-Small-Cell Lung Genetics medicine Humans Neoplastic transformation Phosphorylation Protein kinase A Molecular Biology Protein Kinase Inhibitors Cells Cultured Cell Proliferation Cell growth Kinase c-jun JNK Mitogen-Activated Protein Kinases Epithelial Cells respiratory tract diseases Enzyme Activation Cell Transformation Neoplastic Cancer research Signal transduction Mitogen-Activated Protein Kinases Carcinogenesis Signal Transduction |
| Zdroj: | Oncogene. 26(18) |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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