title: Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial-Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway.
abstract: BACKGROUND
  The cyclooxygenase 2 (COX-2) pathway has been implicated in the molecular pathogenesis of many malignancies, including lung cancer. Apricoxib, a selective COX-2 inhibitor, has been described to inhibit epithelial-mesenchymal transition (EMT) in human malignancies. The mechanism by which apricoxib may alter the tumor microenvironment by affecting EMT through other important signaling pathways is poorly defined. IL-27 has been shown to have anti-tumor activity and our recent study showed that IL-27 inhibited EMT through a STAT1 dominant pathway.
  
  
  OBJECTIVE
  The purpose of this study is to investigate the role of apricoxib combined with IL-27 in inhibiting lung carcinogenesis by modulation of EMT through STAT signaling.
  
  
  RESULTS
  Western blot analysis revealed that IL-27 stimulation of human non-small cell lung cancer (NSCLC) cell lines results in STAT1 and STAT3 activation, decreased Snail protein and mesenchymal markers (N-cadherin and vimentin) and a concomitant increase in expression of epithelial markers (E-cadherin, β-and γ-catenins), and inhibition of cell migration. The combination of apricoxib and IL-27 resulted in augmentation of STAT1 activation. However, IL-27 mediated STAT3 activation was decreased by the addition of apricoxib. STAT1 siRNA was used to determine the involvement of STAT1 pathway in the enhanced inhibition of EMT and cell migration by the combined IL-27 and apricoxib treatment. Pretreatment of cells with STAT1 siRNA inhibited the effect of combined IL-27 and apricoxib in the activation of STAT1 and STAT3. In addition, the augmented expression of epithelial markers, decreased expression mesenchymal markers, and inhibited cell migration by the combination treatment were also inhibited by STAT1 siRNA, suggesting that the STAT1 pathway is important in the enhanced effect from the combination treatment.
  
  
  CONCLUSIONS
  Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell migration in human lung cancer cells through a STAT1 dominant pathway.
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Thoracic Surgery at the David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Mi-Heon
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA ; Division of Thoracic Surgery at the David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Puja
authors.initials: P
authors.lastname: Kachroo
authors.affiliation: Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Pagano
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Thoracic Surgery at the David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Yanagawa
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wang
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA.
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Walser
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA.
authors.forename: Kostyantyn
authors.initials: K
authors.lastname: Krysan
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA ; Molecular Gene Medicine Laboratory, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Maie St
authors.initials: MS
authors.lastname: John
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA ; Molecular Gene Medicine Laboratory, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.affiliation: Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA ; Division of Thoracic Surgery at the David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Lee
keywords: A549; Apricoxib; COX-2; Epithelial-Mesenchymal Transition; IL-27; Non-small cell lung cancer; STAT1; STAT3