NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma

NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma

Cancer cell energy metabolism plays an important role in dictating the efficacy of oncolysis by oncolytic viruses. To understand the role of multiple myeloma metabolism in reovirus oncolysis, we performed semi-targeted mass spectrometry-based metabolomics on 12 multiple myeloma cell lines and reveal...

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Bibliographic Details
Published in:Molecular therapy. Oncolytics Vol. 24; pp. 695 - 706
Main Authors: Kennedy, Barry E., Giacomantonio, Michael, Murphy, J. Patrick, Cutler, Samuel, Sadek, Maryanne, Konda, Prathyusha, Paulo, Joao A., Pathak, Gopal P., Renkens, Saskia H.J., Grieve, Stacy, Pol, Jonathan, Gygi, Steven P., Richardson, Christopher, Gaston, Daniel, Reiman, Anthony, Kroemer, Guido, Elnenaei, Manal O., Gujar, Shashi A.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 17-03-2022
American Society of Gene & Cell Therapy
Elsevier
Subjects:
aerobic glycolysis
autophagy
cancer metabolism
FK866
Medicin och hälsovetenskap
mitochondrial metabolism
NAD
NAMPT
oncolytic virus
Original
p53
reovirus
NAD
cancer metabolism
autophagy
reovirus
oncolytic virus
NAMPT
aerobic glycolysis
FK866
p53
mitochondrial metabolism
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Summary:Cancer cell energy metabolism plays an important role in dictating the efficacy of oncolysis by oncolytic viruses. To understand the role of multiple myeloma metabolism in reovirus oncolysis, we performed semi-targeted mass spectrometry-based metabolomics on 12 multiple myeloma cell lines and revealed a negative correlation between NAD+ levels and susceptibility to oncolysis. Likewise, a negative correlation was observed between the activity of the rate-limiting NAD+ synthesis enzyme NAMPT and oncolysis. Indeed, depletion of NAD+ levels by pharmacological inhibition of NAMPT using FK866 sensitized several myeloma cell lines to reovirus-induced killing. The myelomas that were most sensitive to this combination therapy expressed a functional p53 and had a metabolic and transcriptomic profile favoring mitochondrial metabolism over glycolysis, with the highest synergistic effect in KMS12 cells. Mechanistically, U-13C-labeled glucose flux, extracellular flux analysis, multiplex proteomics, and cell death assays revealed that the reovirus + FK866 combination caused mitochondrial dysfunction and energy depletion, leading to enhanced autophagic cell death in KMS12 cells. Finally, the combination of reovirus and NAD+ depletion achieved greater antitumor effects in KMS12 tumors in vivo and patient-derived CD138+ multiple myeloma cells. These findings identify NAD+ depletion as a potential combinatorial strategy to enhance the efficacy of oncolytic virus-based therapies in multiple myeloma. [Display omitted]
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ISSN:2372-7705
2372-7705
DOI:10.1016/j.omto.2022.02.017