Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE(2)-dependent pathway

作者：Maeng Han Joo; Lee Wook Joo; Jin Qing Ri; Chang Ji Eun; Shim Won Sik^*

来源：European Journal of Pharmaceutical Sciences, 2014, 62: 189-196.

DOI：10.1016/j.ejps.2014.05.023

• Multidrug resistance associated protein 4 (MRP4)
• Cyclooxygenase 2 (COX-2)
• Prostaglandin E2 (PGE(2))
• Lung cancer

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.

• 出版日期2014-10-1
• 单位浙江农林大学