Mi-Heon Lee1, Puja Kachroo2, Paul C Pagano3, Jane Yanagawa1, Gerald Wang4, Tonya C Walser4, Kostyantyn Krysan4, Sherven Sharma5, Maie St John6, Steven M Dubinett7, Jay M Lee2. 1. 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. 2. 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. 3. Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 4. Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, USA ; Division of Pulmonary and Critical Care Medicine, USA. 5. 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. 6. 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. 7. 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.
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. METHODS AND 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. CONCLUSION: 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.
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 humanmalignancies. 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. METHODS AND RESULTS: Western blot analysis revealed that IL-27 stimulation of humannon-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. CONCLUSION: Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell migration in humanlung cancer cells through a STAT1 dominant pathway.
Authors: Guilian Niu; Kenneth L Wright; Mei Huang; Lanxi Song; Eric Haura; James Turkson; Shumin Zhang; Tianhong Wang; Dominic Sinibaldi; Domenico Coppola; Richard Heller; Lee M Ellis; James Karras; Jacqueline Bromberg; Drew Pardoll; Richard Jove; Hua Yu Journal: Oncogene Date: 2002-03-27 Impact factor: 9.867
Authors: Mi-Heon Lee; Jane Yanagawa; Linh Tran; Tonya C Walser; Bharti Bisht; Eileen Fung; Stacy J Park; Gang Zeng; Kostyantyn Krysan; William D Wallace; Manash K Paul; Luc Girard; Boning Gao; John D Minna; Steven M Dubinett; Jay M Lee Journal: Am J Transl Res Date: 2020-02-15 Impact factor: 4.060