Regulation of SOD2 and β-arrestin1 by interleukin-6 contributes to the increase of IGF-1R expression in docetaxel resistant prostate cancer cells.

Abstract

Although several mechanisms behind resistance to docetaxel in castration-refractory prostate cancer (CRPC) have been investigated, molecular determinants of evolved resistance are still not entirely understood. Proteomics-based analysis in this study revealed that SOD2, associated with downregulation of reactive oxygen species (ROS), was significantly up-regulated in docetaxel-resistant (PC3/Doc) cells if compared to sensitive cells, and the expression of redox-regulated genes such as IGF-1R, CXCR4, and BCL2 was increased as well. Forced expression of SOD2 in sensitive cells led to the increase of IGF-1R and association with drug resistance, whereas silencing of SOD2 resulted in the decrease of IGF-1R at the protein level in resistant cells. Further study revealed that SOD2 acted as a negative regulator of β-arrestin1 that is an important adaptor responsible for degradation of IGF-1R via the changes in ROS, as evidenced by observations that an antioxidant agent substantially attenuated β-arrestin1 expression in vitro and in vivo. Finally, we found that blocking of IL6 that was up-regulated in resistant cells resulted in attenuation of SOD2 and STAT3, and simultaneously in increased expression of β-arrestin1. The modulation consequently led to the decreased IGF-1R at both protein and transcription levels. Together, our data provide a novel explanation that high level of IL6 stimulated SOD2 expression that, at least partially, contributed to the low level of ROS that would likely result in a sustained increase in the expression of IGF-1R through abolishment of β-arrestin1 in docetaxel resistant cells.

• Authors: Denglu Zhang, Yazhou Cui, Leilei Niu, Xia Xu, Keli Tian, Charles Y F Young, Hongxiang Lou, Huiqing Yuan
• Journal: European journal of cell biology (Eur J Cell Biol) Vol. 93 Issue 7 Pg. 289-98 (Jul 2014) ISSN: 1618-1298 [Electronic] Germany
• PMID: 24939178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier GmbH. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Arrestins
• BMF protein, human
• CXCR4 protein, human
• Interleukin-6
• Reactive Oxygen Species
• Receptors, CXCR4
• STAT3 Transcription Factor
• STAT3 protein, human
• Taxoids
• beta-Arrestins
• Docetaxel
• Superoxide Dismutase
• superoxide dismutase 2
• Receptor, IGF Type 1

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Antineoplastic Agents (pharmacology)
• Arrestins (metabolism)
• Cell Line, Tumor
• Docetaxel
• Drug Resistance, Neoplasm
• Humans
• Interleukin-6 (metabolism)
• Male
• Prostatic Neoplasms (genetics, pathology)
• Reactive Oxygen Species (metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)
• Receptors, CXCR4 (metabolism)
• STAT3 Transcription Factor (metabolism)
• Superoxide Dismutase (genetics, metabolism)
• Taxoids (pharmacology)
• Up-Regulation
• beta-Arrestins