Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial-Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway
Mi-Heon Lee1,3#, Puja Kachroo1-3#, Paul C Pagano4, Jane Yanagawa1,3, Gerald Wang1,2, Tonya C Walser1,2, Kostyantyn Krysan1,2, Sherven Sharma1,5,6, Maie St. John1,5, Steven M Dubinett1,2,6 and Jay M Lee1-3*
- *Corresponding Author:
- Jay M Lee
Division of Thoracic Surgery, Ronald Reagan UCLA Medical Center
Box 957313, Room 64-128 CHS, 10833 Le Conte Ave
Los Angeles CA, 90095-7313, USA
Tel: (310) 794-7333
Fax: (310) 794-7335
E-mail: [email protected]
Received date: August 21, 2014; Accepted date: November 12, 2014; Published date: November 15, 2014
Citation: Lee MH, Kachroo P, Pagano PC, Yanagawa J, Wang G, et al. (2014) Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial- Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway. J Cancer Sci Ther 6:468-477. doi:10.4172/1948-5956.1000310
Copyright: © 2014 Lee MH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.