title: JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling.
abstract: Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases. We examined STAT protein activation in lung cancer cell lines including those with activating mutations in the EGFR and examined upstream kinases responsible for STAT3 phosphorylation and activation using small molecules, antibodies, and RNA interference. We found more pronounced STAT3 activation in cells with activating EGFR mutations, yet inhibition of EGFR activity had no effect on STAT3 activation. Inhibition of JAK1 with small molecules or RNA interference resulted in loss of STAT3 tyrosine phosphorylation and inhibition of cell growth. An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner. Siltuximab could completely inhibit STAT3 tyrosine phosphorylation in H1650 cells, and this resulted in inhibition of lung cancer cell growth in vivo. Combined EGFR inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine STAT3 phosphorylation, more pronounced inhibition of STAT3 transcriptional activity, and translated into combined effects on lung cancer growth in a mouse model. Our results suggest that JAK1 is responsible for STAT3 activation in lung cancer cells and that indirect attacks on JAK1-STAT3 using an IL-6 neutralizing antibody with or without EGFR inhibition can inhibit lung cancer growth in lung cancer subsets.
authors.affiliation: Thoracic Oncology and Experimental Therapeutics Programs H. Lee Moffitt Cancer Center and Research Institute MRC3 East, Room 3056F, 12902 Magnolia Drive Tampa, Florida 33612-9497, USA.
authors.forename: Lanxi
authors.initials: L
authors.lastname: Song
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Rawal
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nemeth
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000276:immunology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010766:Phosphorylation; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D066246:ErbB Receptors; D015850:Interleukin-6; D053613:Janus Kinase 1; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C494087:Stat3 protein, mouse; C507905:Jak1 protein, mouse; C504234:siltuximab