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

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

doi:10.1016/j.canlet.2010.02.019

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Volume 295, Issue 1 , Pages 110-123, 1 September 2010

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

Yue Wang
- Department of Immunology, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China
- Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard, Tianjin, People’s Republic of China
- Corresponding author. Address: Department of Immunology, Medical College of Chinese People’s Armed Police Forces, Hedong District Chenlin Road No. 211, Tianjin 300162, People’s Republic of China. Tel.: +86 22 60578099; fax: +86 22 022 24799262.
Xiu Long Niu
- Department of Immunology, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China
Ye Qu
- Department of Microbiology, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China
Jian Wu
- Department of Immunology, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China
Ya Qin Zhu
- Department of Immunology, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China
Wei Jia Sun
- Department of Immunology, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China
Ling Zhi Li
- Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard, Tianjin, People’s Republic of China
- Department of Pharmaceutical Chemistry, Medical College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China

Received 5 December 2009; received in revised form 19 February 2010; accepted 19 February 2010. published online 17 March 2010.

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.

Keywords: Interleukin-6 (IL-6), Chemoresistance, Multidrug resistance-related genes, Apoptosis inhibitory proteins, Ovarian cancer