Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathy
PublisherSAGE Publications Inc.
MetadataShow full item record
AbstractChemotherapy-induced painful peripheral neuropathy is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which chemotherapy-induced painful peripheral neuropathy develops have remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha is a transcription factor that is known to reprogram cellular metabolism. Furthermore, hypoxia-inducible factor 1 alpha protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilizes the expression of hypoxia-inducible factor 1 alpha leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilizes the expression of hypoxia-inducible factor 1 alpha. Moreover, knockdown of hypoxia-inducible factor 1 alpha, inhibition of hypoxia-inducible factor 1 alpha binding to its response element, or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of hypoxia-inducible factor 1 alpha expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of hypoxia-inducible factor 1 alpha expression as the molecular mechanism by which bortezomib initiates chemotherapy-induced painful peripheral neuropathy. Crucially, these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms. Copyright The Author(s) 2019.
SponsorsThis work is supported by grant from the Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore (OKM), and Future Leaders in Pain Research, American Pain Society (OKM).
chemotherapy-induced painful peripheral neuropathy
dorsal root ganglion
hypoxia-inducible factor 1 alpha
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85065676479&doi=10.1177%2f1744806919850043&partnerID=40&md5=4f4f9d5533879a030e7cdd9c1a1cbbd0; http://hdl.handle.net/10713/10186
- Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy.
- Authors: Ludman T, Melemedjian OK
- Issue date: 2019 Jan-Dec
- Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord.
- Authors: Xie JD, Chen SR, Chen H, Pan HL
- Issue date: 2017 Sep 1
- Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain.
- Authors: Li C, Deng T, Shang Z, Wang D, Xiao Y
- Issue date: 2018
- Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse.
- Authors: Carozzi VA, Renn CL, Bardini M, Fazio G, Chiorazzi A, Meregalli C, Oggioni N, Shanks K, Quartu M, Serra MP, Sala B, Cavaletti G, Dorsey SG
- Issue date: 2013
- Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy.
- Authors: Zheng H, Xiao WH, Bennett GJ
- Issue date: 2012 Dec