title: JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer.
abstract: Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non-small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here, we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a c-JUN-NH2-kinase (JNK) inhibitor, recapitulated defects in EPHA2-deficient tumor cells, whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem-like cells (CSC). RNA interference-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH(+) cancer stem-like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH(+) populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung CSCs. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in CSC function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC. Cancer Res; 74(9); 2444-54. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Veterans Affairs Medical Center, Tennessee Valley Healthcare System; Division of Rheumatology and Immunology, Department of Medicine; Departments of Neurological Surgery, Cancer Biology, and Cell and Developmental Biology; and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Song
authors.forename: Yufang
authors.initials: Y
authors.lastname: Ma
authors.forename: Jialiang
authors.initials: J
authors.lastname: Wang
authors.forename: Dana
authors.initials: D
authors.lastname: Brantley-Sieders
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D063646:Carcinogenesis / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D036104:Receptor, EphA2 / Q000502:physiology*; D047368:Tumor Burden
chemical_list: D000873:Anthracenes; C432165:pyrazolanthrone; D000444:Aldehyde Dehydrogenase; D036104:Receptor, EphA2; D048031:JNK Mitogen-Activated Protein Kinases