Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain

Abstract

BACKGROUND: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established. METHODS: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests RESULTS: PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain–containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain. CONCLUSIONS: pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.

Melatonin Relieves Paclitaxel-Induced Neuropathic Pain by Regulating pNEK2-Dependent Epigenetic Pathways in DRG Neurons

“…MLT profoundly impacts the epigenetic regulation of gene expression, suggesting its potential utility in combination therapy with epigenetic drugs, presenting a novel approach to anticancer treatment . Our prior research revealed that the chemotherapy drug PTX heightened a pNEK2-dependent epigenetic process within the DRG, contributing to the development of neuropathic pain, a major side effect of PTX . Specifically, pRSK2 initiated the expression of pNEK2, leading to a reduction in H3K27me3 levels by increasing the JMJD3 activity.…”

“…22 Our prior research revealed that the chemotherapy drug PTX heightened a pNEK2-dependent epigenetic process within the DRG, contributing to the development of neuropathic pain, a major side effect of PTX. 15 Specifically, pRSK2 initiated the expression of pNEK2, leading to a reduction in H3K27me3 levels by increasing the JMJD3 activity. This cascade of events resulted in the upregulation of TRPV1 gene transcription within the DRGs, which is a critical factor in PTX-induced neuropathic pain.…”

“…This evidence indicated that MLT may regulate microtubules to relieve PTX-induced neuropathic pain. It is worth noting that our recent study demonstrated that a microtubule regulator phosphorylated NEK2 (pNEK2)-dependent epigenetic pathway in DRG neurons mediates PTX-induced neuropathic pain . At the molecular level, PTX-induced activation of p90 ribosomal S6 kinase 2 phosphorylation (pRSK2) leads to activation of pNEK2.…”

“…It is worth noting that our recent study demonstrated that a microtubule regulator phosphorylated NEK2 (pNEK2)-dependent epigenetic pathway in DRG neurons mediates PTX-induced neuropathic pain. 15 At the molecular level, PTX-induced activation of p90 ribosomal S6 kinase 2 phosphorylation (pRSK2) leads to activation of pNEK2. Subsequently, pNEK2 upregulates the expression of jumonji domain-containing 3 (JMJD3), a histone demethylase.…”

Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion

“…5 Furthermore, our previous study demonstrated that 1 spinal PRMT family member is involved in neuropathic pain 6 and that the histone methylation regulation of nociceptive gene expression in DRG neurons plays a key role in PTX-induced neuropathic pain. 7 Thus, increased PRMT5 expression in the DRG may be involved in PTX-induced neuropathic pain.…”