Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy.

Abstract

Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

• Authors: Laura Rullo, Silvia Franchi, Giada Amodeo, Francesca Felicia Caputi, Benedetta Verduci, Loredana Maria Losapio, Paola Sacerdote, Patrizia Romualdi, Sanzio Candeletti
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 21 (Nov 03 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34769347 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cytokines
• Gastrointestinal Hormones
• Neuropeptides
• PPAR alpha
• PPAR gamma
• Ppara protein, mouse
• Pparg protein, mouse
• Prok2 protein, mouse
• Bortezomib
• Histone Demethylases
• Utx protein, mouse

Topics

• Animals
• Antineoplastic Agents (toxicity)
• Bortezomib (toxicity)
• Cytokines (metabolism)
• Gastrointestinal Hormones (genetics, metabolism)
• Histone Demethylases (genetics, metabolism)
• Hyperalgesia (chemically induced, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Neuropeptides (genetics, metabolism)
• PPAR alpha (genetics, metabolism)
• PPAR gamma (genetics, metabolism)
• Pain (chemically induced, genetics, metabolism, pathology)
• Peripheral Nervous System Diseases (chemically induced, genetics, metabolism, pathology)
• Spinal Cord (metabolism, pathology)