Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy
PublisherSAGE Publications Inc.
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AbstractChemotherapy-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.
SponsorsThis 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).
Identifier to cite or link to this itemhttps://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
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