title: Leukotriene B4 receptor-2 contributes to chemoresistance of SK-OV-3 ovarian cancer cells through activation of signal transducer and activator of transcription-3-linked cascade.
abstract: Inflammation and inflammatory mediators are intimately linked with chemoresistance through complex pathways in the tumor microenvironment. However, the mechanism by which inflammatory mediators (e.g., eicosanoids) contribute to chemoresistance remains elusive. In this study, we found that the low-affinity leukotriene B4 receptor-2 (BLT2) and its ligand leukotriene B4 were highly up-regulated in cisplatin-resistant SK-OV-3 ovarian cancer cells and play critical roles in mediating the chemoresistance through the activation of signal transducer and activator of transcription-3 (STAT-3) and the subsequent up-regulation of interleukin-6 (IL-6). BLT2 depletion with siRNA clearly abolished the chemoresistance to cisplatin in SK-OV-3 ovarian cancer cells and further increased cell sensitivity to cisplatin chemotherapy by down-regulating the 'STAT-3-IL-6' cascade. Enlarged tumor formation due to the cisplatin resistance of SK-OV-3 cells in cisplatin-treated athymic mice was also substantially reduced by co-treatment with the BLT2 inhibitor in vivo. Our study demonstrates that BLT2 is a novel contributor to cisplatin resistance in SK-OV-3 ovarian cancer cells and thus may be a potential therapeutic target for the treatment of cisplatin-resistant ovarian cancer.
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: JaeIn
authors.initials: J
authors.lastname: Park
authors.affiliation: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea. Electronic address: jhongkim@korea.ac.kr.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; C485878:LTB4R2 protein, human; D020024:Leukotriene Antagonists; D018102:Receptors, Leukotriene B4; D050796:STAT3 Transcription Factor; D013777:Tetrazoles; C063823:LY 255283; D002945:Cisplatin
keywords: BLT2; Chemoresistance; Cisplatin; Ovarian cancer; SK-OV-3 cells; STAT-3