title: Autocrine IL-8 and VEGF mediate epithelial-mesenchymal transition and invasiveness via p38/JNK-ATF-2 signalling in A549 lung cancer cells.
abstract: Soluble factors in tumour microenvironment play a major role in modulating the metastatic potential of cancer cells. Herein, we investigated the effect of autocrine cytokines and growth factors in the form of self-conditioned medium (CM) on A549 lung carcinoma cells. We demonstrated that CM induced morphological and molecular changes associated with epithelial-mesenchymal transition viz change in shape from cuboidal to spindle, actin cytoskeleton remodelling, upregulation of vimentin and downregulation of E-cadherin etc. These changes were accompanied with enhanced motility, invasion, anchorage-independent growth and anoikis-resistance. Amongst the different factors of CM, IL-8 and VEGF were found to play a major role in the CM-induced motility and invasion. In the intracellular signalling cascade, CM triggered phosphorylation of JNK and p38 which was associated with the CM-enhanced invasiveness. In CM-treated cells, activated p38 and JNK further activated ATF-2 (Activating Transcription Factor-2) and knock-down of ATF-2 abrogated the CM-induced invasiveness, suggesting the signal transduction along the p38/JNK-ATF-2 axis. Furthermore, neutralising IL-8 and VEGF in CM, significantly abrogated CM-induced phosphorylation of ATF-2. Conversely, exogenous addition of these individual cytokines in plain medium, increased the activation of ATF-2 and invasiveness marginally. However, when added in combination these cytokines (IL-8 and VEGF) resulted in drastic increase in ATF-2 phosphorylation and subsequent invasiveness suggesting their synergetic interplay in the observed phenomenon. Taken together, our results identify IL-8/VEGF induced JNK/p38-ATF-2 as a novel pro-invasive pathway, which may be explored as potential therapeutic target to circumvent the invasiveness of lung malignancies.
authors.affiliation: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: Sejal
authors.initials: S
authors.lastname: Desai
authors.forename: S
authors.initials: S
authors.lastname: Laskar
authors.forename: B N
authors.initials: BN
authors.lastname: Pandey
mesh_terms: D051698:Activating Transcription Factor 2 / Q000276:immunology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases