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    Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathy

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    Author
    Ludman, T.
    Melemedjian, O.K.
    Date
    2019
    Journal
    Molecular Pain
    Publisher
    SAGE Publications Inc.
    Type
    article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1177/1744806919850043
    Abstract
    Chemotherapy-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.
    Sponsors
    This 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).
    Keyword
    aerobic glycolysis
    chemotherapy-induced painful peripheral neuropathy
    dorsal root ganglion
    hypoxia-inducible factor 1 alpha
    metformin
    Neuropathy
    Identifier to cite or link to this item
    https://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
    ae974a485f413a2113503eed53cd6c53
    10.1177/1744806919850043
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