Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells

Yue Wang; Xiu Long Niu; Ye Qu; Jian Wu; Ya Qin Zhu; Wei Jia Sun; Ling Zhi Li

doi:10.1016/j.canlet.2010.02.019

Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells

Cancer Lett. 2010 Sep 1;295(1):110-23. doi: 10.1016/j.canlet.2010.02.019. Epub 2010 Mar 16.

Authors

Yue Wang¹, Xiu Long Niu, Ye Qu, Jian Wu, Ya Qin Zhu, Wei Jia Sun, Ling Zhi Li

Affiliation

¹ Department of Immunology, Medical College of Chinese People's Armed Police Forces, Tianjin, People's Republic of China. wy68wy68@yahoo.com.cn

PMID: 20236757
DOI: 10.1016/j.canlet.2010.02.019

Abstract

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cisplatin / pharmacology*
Cytokine Receptor gp130 / metabolism
Drug Resistance, Neoplasm*
Female
Gene Expression Regulation, Neoplastic
Glutathione S-Transferase pi / genetics
Glutathione S-Transferase pi / metabolism
Humans
Interleukin-6 / metabolism*
Interleukin-6 / pharmacology
Mitogen-Activated Protein Kinases / metabolism
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism*
Paclitaxel / pharmacology*
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Receptors, Interleukin-6 / metabolism
Signal Transduction / drug effects
X-Linked Inhibitor of Apoptosis Protein / genetics
X-Linked Inhibitor of Apoptosis Protein / metabolism
bcl-X Protein / genetics
bcl-X Protein / metabolism
raf Kinases / metabolism
ras Proteins / metabolism

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
BCL2L1 protein, human
IL6ST protein, human
Interleukin-6
Proto-Oncogene Proteins c-bcl-2
Receptors, Interleukin-6
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human
bcl-X Protein
interleukin-6 receptor alpha
Cytokine Receptor gp130
Glutathione S-Transferase pi
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
raf Kinases
Mitogen-Activated Protein Kinases
ras Proteins
Paclitaxel
Cisplatin