title: Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy.
abstract: Bortezomib (BTZ) is a frequently used chemotherapeutic drug for the treatment of refractory multiple myeloma and hematological neoplasms. The mechanism by which the administration of BTZ leads to painful peripheral neuropathy remains unclear. In present study, we found that application of BTZ at 0.4 mg/kg for consecutive 5 days significantly increased the expression of CCL2 in DRG, and intrathecal administration of neutralizing antibody against CCL2 inhibited the mechanical allodynia induced by BTZ. We also found an increased expression of c-Jun in DRG, and that inhibition of c-Jun signaling prevented the CCL2 upregulation and mechanical allodynia in the rats treated with BTZ. Furthermore, the results with luciferase assay in vitro and ChIP assay in vivo showed that c-Jun might be essential for BTZ-induced CCL2 upregulation via binding directly to the specific position of the ccl2 promoter. In addition, the present results showed that an upregulated expression of ATF3 was co-expressed with c-Jun in the DRG neurons, and the enhanced interaction between c-Jun and ATF3 was observed in DRG in the rats treated with BTZ. Importantly, pretreatment with ATF3 siRNA significantly inhibited the recruitment of c-Jun to the ccl2 promoter in the rats treated with BTZ. Taken together, these findings suggested that upregulation of CCL2 resulting from the enhanced interaction between c-Jun and ATF3 in DRG contributed to BTZ-induced mechanical allodynia.
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou 510120, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou 510120, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Luan
authors.affiliation: Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen Universtiy Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Handong
authors.initials: H
authors.lastname: OuYang
authors.affiliation: Department of Physiology and Pain Research Center, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan Medical School, Sun Yet-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou 510120, China.
authors.forename: Shaoling
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou 510120, China. Electronic address: ma_chao99@126.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Physiology and Pain Research Center, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan Medical School, Sun Yet-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.
authors.forename: Jiayou
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Physiology and Pain Research Center, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan Medical School, Sun Yet-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China. Electronic address: xinwj@mail.sysu.edu.cn.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xin
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib / Q000009:adverse effects* / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; C497108:Atf3 protein, rat; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D000069286:Bortezomib; D048031:JNK Mitogen-Activated Protein Kinases
keywords: ATF3; Allodynia; Bortezomib; CCL2; c-Jun