Abstract 310: The role of c-Jun N-terminal kinase 2alpha in non-small cell lung carcinoma tumorigenesis

c-Jun N-terminal kinases (JNKs) are members of the mitogen activated protein kinase (MAPK) family and have been implicated in tumorigenesis. One isoform in particular, JNK2alpha, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes, and to increase tumor formation in mice. It was reported that there is frequent activation of JNK in non-small cell lung carcinoma (NSCLC). In this study, we investigated the role of the JNK2alpha isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered 70% of the tested primary NSCLC tumors had 2 to 3-fold higher JNK2alpha protein and mRNA expression compared to normal lung tissue indicating a possible role of JNK2alpha in NSCLC tumorigenesis. To determine the importance of JNK2alpha in NSCLC progression, we reduced JNK2α in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2alpha had decreased cellular growth and anchorage-independent growth, and the tumors were 4-fold smaller in mass. To elucidate the mechanism by which JNK2alpha induces NSCLC growth, we analyzed the JNK substrate, STAT3. Our data show that JNK2alpha can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue of STAT3 thereby regulating expression of oncogenic genes, such as c-Myc protein. Our studies revealed a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2alpha. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 310.