Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells.
It has been shown that IL-6 is elevated in the serum and ascites of ovarian cancer patients, and increased IL-6 concentration correlates with poor prognosis and chemoresistance. However, the role of IL-6 expression in the acquisition of the chemoresistance phenotype and the underlining mechanisms of drug resistance in ovarian cancer cells remain unclear. Here we demonstrate that both exogenous (a relatively short period of treatment with recombination IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells, while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) promotes the sensitivity of these cells to anticancer drugs. IL-6-mediated resistance of ovarian cancer cells exhibits decreased proteolytic activation of caspase-3. Meanwhile, the further study demonstrates that the chemoresistance caused by IL-6 is associated with increased expression of both multidrug resistance-related genes (MDR1 and GSTpi) and apoptosis inhibitory proteins (Bcl-2, Bcl-xL and XIAP), as well as activation of Ras/MEK/ERK and PI3K/Akt signaling. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer.
Wang
Yue
Y
Department of Immunology, Medical College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China. wy68wy68@yahoo.com.cn
Niu
Xiu Long
XL
Qu
Ye
Y
Wu
Jian
J
Zhu
Ya Qin
YQ
Sun
Wei Jia
WJ
Li
Ling Zhi
LZ
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494199:IL6ST protein, human; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D019947:Receptors, Interleukin-6; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; D051549:Glutathione S-Transferase pi; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D017239:Paclitaxel; D002945:Cisplatin