title: 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.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China; Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan 250012, China.
authors.forename: Denglu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Academy of Medical Sciences, Jinan 250012, China.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Niu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Keli
authors.initials: K
authors.lastname: Tian
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Charles Y F
authors.initials: CY
authors.lastname: Young
authors.affiliation: Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan 250012, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China. Electronic address: lyuanhq@sdu.edu.cn.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Yuan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D015854:Up-Regulation; D000071557:beta-Arrestins; D000099156:Superoxide Dismutase 2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019390:Arrestins; D000077143:Docetaxel; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D017526:Receptor, IGF Type 1; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D043823:Taxoids; D000071557:beta-Arrestins; D000099156:Superoxide Dismutase 2; C486655:BMF protein, human; C527276:CXCR4 protein, human; C494086:STAT3 protein, human
keywords: Beta-arrestin1; Drug resistance; IGF-1R; Prostate cancer; SOD2