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The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis

Oncogene volume 30, pages 234–244 (2011)Cite this article

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Abstract

The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family and have been implicated in tumorigenesis. One isoform in particular, JNK2α, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes and to increase tumor formation in mice. As JNK is frequently activated in non-small cell lung carcinoma (NSCLC), we investigated the role of the JNK2α isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered that 60% of the tested primary NSCLC tumors had three-fold higher JNK2 protein and two- to three-fold higher JNK2α mRNA expression than normal lung control tissue. To determine the importance of JNK2α in NSCLC progression, we reduced JNK2α expression in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2α had decreased cellular growth and anchorage-independent growth, and the tumors were four-fold smaller in mass. To elucidate the mechanism by which JNK2α induces NSCLC growth, we analyzed the JNK substrate, signal transducer and activator of transcription 3 (STAT3). Our data demonstrates for the first time that JNK2α can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue, thereby regulating the expression of oncogenic genes, such as c-Myc. Furthermore, reintroduction of JNK2α2 or STAT3 restored the tumorigenicity of the NSCLC cells, demonstrating that JNK2α is important for NSCLC progression. Our studies reveal a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2α.

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Acknowledgements

We are grateful to Emily Piccione, Shawn Badal, Tiffany Lieu and Marina Holgado-Madruga for their useful discussions and critical review of the paper. This work was supported by the Mark Linder/American Brain Tumor Association Fellowship, NIH grants CA69495 and CA124832 and a research grant from the National Brain Tumor Foundation.

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Authors and Affiliations

  1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

    R T Nitta, C A Del Vecchio, A H Chu, S S Mitra & A J Wong

  2. Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA

    C A Del Vecchio & A J Wong

  3. Department of Medical Oncology, Women's Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    A K Godwin

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  1. R T Nitta
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Correspondence to A J Wong.

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Nitta, R., Del Vecchio, C., Chu, A. et al. The role of the c-Jun N-terminal kinase 2-α-isoform in non-small cell lung carcinoma tumorigenesis. Oncogene 30, 234–244 (2011). https://doi.org/10.1038/onc.2010.414

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