NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

Abstract

Background: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods: Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, microarray analysis were performed to explore the molecular mechanism. Results: We found that paclitaxel treatment increased the expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TSS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy directly upregulated the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion: These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

Downregulation of metallothionein-2 contributes to oxaliplatin-induced neuropathic pain

“…Other laboratories have also reported complementary findings on the direct central nerve system (CNS) effects of chemotherapeutic paclitaxel [ 13 , 14 ], and neuropathological changes in the spinal dorsal horn neurons have therefore gained significant interest [ 15 , 16 ]. Like the peripheral neuropathological changes that occur in dorsal root ganglion neurons and distal nerve endings, the central effects of very low concentrations of chemotherapeutics are associated with the development of overt CIPN [ 8 , 17 ]. Also, like the well-documented peripheral effects, no clear preventative treatment exists, and the underlying mechanisms need further investigation.…”

Upregulation of LncRNA71132 in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain

“…44 It is well-known that upregulation of CXCL14 and activation of ERK1/2 or AKt can promote neuronal excitability through the initiation of an inflammatory response. 13,25 However, there is a need for further studies on whether or not expression of GPR85 of the spinal cord is regulated by these CXCL14 and signaling pathways in BCP.…”

Upregulation of the oxytocin receptor in dorsal root ganglion mediated peripheral analgesia of oxytocin in chemotherapy-induced peripheral neuropathic pain

“…PTX induced mitochondria damage and reactive oxygen species production may result in activation of NLRP3 in ammasome in peripheral nerve, which in turn contributed to the development of neuropathic pain [9]. It is reported that the epigenetic upregulation of CXCL14 in the spinal dorsal horn contributed to the PTXinduced neuropathic pain [11]. Additionally, it has been also reported that multiple ion channels in DRG neurons are involved [13,14].…”

“…The mechanism underlying PTX-induced neuropathic pain is complicated andrecent ndings suggested thatPTX-induced peripheral neuropathy is often associated with neuroin ammation in the peripheral nervous system [9][10][11]. For example, compared with control rats, it is found that plasma levels of IL-1α, IL-1β, IL-6, TNF-α, INF-γ and MCP-1 were signi cantly upregulated in PTX-treated rats [12].…”