Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE(2)-dependent pathway
- Authors
- Maeng, Han-Joo; Lee, Wook-Joo; Jin, Qing-Ri; Chang, Ji-Eun; Shim, Won-Sik
- Issue Date
- Oct-2014
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Multidrug resistance associated protein 4 (MRP4); Cyclooxygenase 2 (COX-2); Prostaglandin E2 (PGE(2)); Lung cancer
- Citation
- EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, v.62, pp.189 - 196
- Journal Title
- EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
- Volume
- 62
- Start Page
- 189
- End Page
- 196
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/12211
- DOI
- 10.1016/j.ejps.2014.05.023
- ISSN
- 0928-0987
- Abstract
- It is apparent that lung cancer is associated with inflammation, with accompanying hallmark elevations of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE(2)) levels. However, the effects of these changes on MRP efflux transporters have not been thoroughly investigated before. Here, we report that upregulation of COX-2 can induce overexpression of MRP4 in both A549 non-small-cell lung cancer cell lines and mouse lung cancer models. In A549 cells, phorbol 12-myristate 13-acetate (PMA) treatment induced upregulation of COX-2 and MRP4 together, but not other MRP transporters. Transient overexpression of human COX-2 cDNA also specifically increased COX-2 and MRP4. Moreover, COX inhibitor treatment and COX-2-specific siRNA significantly inhibited the upregulation of MRP4. Additionally, PMA-treatment increased extracellular PGE(2) levels, likely due to increased MRP4 function. Likewise, COX-2-specific siRNA reduced extracellular PGE(2) levels. Furthermore, COX-2 upregulation resulted in an increase in mPGES-1, an enzyme responsible for PGE(2) production. Finally, metastasized lung cancer model mice exhibited increased expression levels of COX-2 and MRP4, as well as mPGES-1. In conclusion, the present study suggests that overexpression of MRP4 in lung cancer may be attributable to COX-2 upregulation via a PGE(2)-dependent pathway. (C) 2014 Elsevier B.V. All rights reserved.
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