title: [Chemotherapy resistance induced by interleukin-6 in ovarian cancer cells and its signal transduction pathways].
abstract: OBJECTIVE
  To study the mechanism of chemotherapy resistance caused by interleukin-6 (IL-6) in ovarian cancer cells and its related signal pathways.
  
  
  METHODS
  Ovarian cancer cell lines A2780 (IL-6 receptor positive, while non-IL-6-expressing and cisplatin/paclitaxel-responsive) and SKOV3 cell lines (overexpressing of IL-6 receptor and IL-6 and cisplatin/paclitaxel-resistant) were suitable models for this study. The effect of exogenous (a short period of treatment with recombination IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) in A2780 cells or deleting of endogenous IL-6 expression in SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) on the sensitivity to cisplatin and paclitaxel was investigated. Meanwhile, the mechanism of chemotherapy resistance caused by IL-6 in ovarian cancer cells and its related signal pathways were also analyzed.
  
  
  RESULTS
  We found that both exogenous and endogenous IL-6 induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells (the resistance multiple to cisplatin and paclitaxel was: exogenous, 6.25 and 7.31; endogenous, 7.13-8.34 and 7.61-10.70), while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells promotes its sensitivity to anticancer drugs (the resistance multiple to cisplatin and paclitaxel was 0.15 and 0.10, 0.10 and 0.08). IL-6 significantly up-regulated the expression levels of mRNA and protein of drug resistance-associated genes, MDR1 and GST-π, and apoptosis-inhibiting genes, bcl-2, bcl-xL and XIAP in a dose-dependent manner in A2780 cells. In accordance with this finding, the mRNA and protein levels of MDR1 and GST-π enhanced in sense IL-6-transfected A2780 cells, and reduced in antisense IL-6-transfected SKOV3 cells compared with the corresponding parental and control vector-transfected cells, which had no difference. It was found that PD98059 [mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK) inhibitor] and wortmannin [phosphatidylinositol 3-kinase (PI3K) inhibitor] significantly antagonized IL-6-induced phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), respectively, and both of them blocked IL-6-induced cisplatin and paclitaxel resistance and the inhibitory effects of PD98059 and wortmannin were dependent on its concentration.
  
  
  CONCLUSIONS
  These data suggest that IL-6-induced chemoresistance may be associated with increase of both drug resistance-associated genes (MDR1 and GST-π) and apoptosis-inhibiting genes (bcl-2, bcl-xL and XIAP), and activation of MEK/ERK and PI3K/Akt. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer.
authors.affiliation: Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard, Tianjin 300162, China. wy68wy68@yahoo.com.cn
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Ling-zhi
authors.initials: LZ
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Ye
authors.forename: Xiu-long
authors.initials: XL
authors.lastname: Niu
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Ya-qin
authors.initials: YQ
authors.lastname: Zhu
authors.forename: Wei-jia
authors.initials: WJ
authors.lastname: Sun
authors.forename: Yan-jun
authors.initials: YJ
authors.lastname: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002945:Cisplatin; D015850:Interleukin-6; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D012333:RNA, Messenger