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    Bortezomib-induced aerobic glycolysis contributes to 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/10.1177/1744806919837429
    Abstract
    Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN. Copyright The Author(s) 2019.
    Sponsors
    This work was supported by the Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore (to OKM) and Future Leaders in Pain Research, American Pain Society (to OKM).
    Keyword
    aerobic glycolysis
    CIPN
    DRG
    metabolism
    mitochondria
    Neuropathy
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85064001569&doi=10.1177%2f1744806919837429&partnerID=40&md5=7abe7bf10237be6ae79b2868e19769bc; http://hdl.handle.net/10713/10185
    ae974a485f413a2113503eed53cd6c53
    10.1177/1744806919837429
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