title: Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE2-dependent pathway.
abstract: It is apparent that lung cancer is associated with inflammation, with accompanying hallmark elevations of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) 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 PGE2 levels, likely due to increased MRP4 function. Likewise, COX-2-specific siRNA reduced extracellular PGE2 levels. Furthermore, COX-2 upregulation resulted in an increase in mPGES-1, an enzyme responsible for PGE2 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 PGE2-dependent pathway.
authors.affiliation: College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam, South Korea.
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.affiliation: College of Pharmacy, Gachon University, Hambakmoeiro 191, Yeonsu-gu, Incheon 406-799, South Korea.
authors.forename: Wook-Joo
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: College of Animal Science and Technology, Zhejiang A&F University, Lin'an, Zhejiang Province, China.
authors.forename: Qing-Ri
authors.initials: QR
authors.lastname: Jin
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Seoul National University, Bundang Hospital, Seongnam, Gyeonggi, South Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Gachon University, Hambakmoeiro 191, Yeonsu-gu, Incheon 406-799, South Korea. Electronic address: wsshim@gachon.ac.kr.
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D018076:DNA, Complementary / Q000008:administration & dosage; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D051546:Cyclooxygenase 2; D018076:DNA, Complementary; D015232:Dinoprostone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013755:Tetradecanoylphorbol Acetate; C073492:ABCC4 protein, human; C489540:Abcc4 protein, mouse; C077623:Ptgs2 protein, mouse; C496540:PTGS2 protein, human
keywords: Cyclooxygenase 2 (COX-2); Lung cancer; Multidrug resistance associated protein 4 (MRP4); Prostaglandin E2 (PGE(2))