Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy

• Painful peripheral neuropathy induced by chemotherapy drugs often serves as the common reason for treatment discontinuation or dose reduction rather than tumor progression, the underlying mechanism in the Bortezomib-induced painful peripheral neuropathy remains unclear.
• Here we found that upregulated CCL2 expression in DRGs was critical to the development of BTZ-induced mechanical allodynia.
• Furthermore, c-Jun might be essential for BTZ-induced CCL2 upregulation via binding directly to the specific position of the ccl2 promoter.
• Finally, c-Jun and ATF3 interaction might contribute to the enhanced transcription of ccl2 after BTZ treatment.
• Our findings revealed a novel mechanism underlying Bortezomib-induced painful peripheral neuropathy.

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.