NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma

Barry E. Kennedy; Michael Giacomantonio; J. Patrick Murphy; Samuel Cutler; Maryanne Sadek; Prathyusha Konda; Joao A. Paulo; Gopal P. Pathak; Saskia H.J. Renkens; Stacy Grieve; Jonathan Pol; Steven P. Gygi; Christopher Richardson; Daniel Gaston; Anthony Reiman; Guido Kroemer; Manal O. Elnenaei; Shashi A. Gujar

Molecular Therapy: Oncolytics (Mar 2022)

NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma

Barry E. Kennedy,
Michael Giacomantonio,
J. Patrick Murphy,
Samuel Cutler,
Maryanne Sadek,
Prathyusha Konda,
Joao A. Paulo,
Gopal P. Pathak,
Saskia H.J. Renkens,
Stacy Grieve,
Jonathan Pol,
Steven P. Gygi,
Christopher Richardson,
Daniel Gaston,
Anthony Reiman,
Guido Kroemer,
Manal O. Elnenaei,
Shashi A. Gujar

Affiliations

Barry E. Kennedy: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada
Michael Giacomantonio: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada
J. Patrick Murphy: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada; Department of Biology, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada
Samuel Cutler: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada
Maryanne Sadek: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada
Prathyusha Konda: Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 1X5, Canada
Joao A. Paulo: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Gopal P. Pathak: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada
Saskia H.J. Renkens: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada
Stacy Grieve: Department of Biology, University of New Brunswick, Saint John E2L 4L2, Canada
Jonathan Pol: Gustave Roussy Comprehensive Cancer Institute, Villejuif 94800, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif 94800, France; INSERM, U1138, Paris 75006, France; Équipe 11 labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris 75006, France; Université de Paris, Paris 75006, France; Sorbonne Université, Paris 75006, France
Steven P. Gygi: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Christopher Richardson: Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 1X5, Canada; Department of Pediatrics, Dalhousie University, Halifax, NS B3H 1X5, Canada
Daniel Gaston: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada; Department of Pathology and Laboratory Medicine, Nova Scotia Health Authority (NSHA), Halifax, NS B3H 1V8, Canada; Department of Pathology, Dalhousie University, Halifax, NS B3H 1V8, Canada
Anthony Reiman: Department of Biology, University of New Brunswick, Saint John E2L 4L2, Canada; Department of Oncology, University of New Brunswick, Saint John E2L 4L2, Canada; Department of Medicine, Dalhousie University, Halifax, NS B3H 1X5, Canada
Guido Kroemer: Department of Pathology and Laboratory Medicine, Nova Scotia Health Authority (NSHA), Halifax, NS B3H 1V8, Canada; Department of Pathology, Dalhousie University, Halifax, NS B3H 1V8, Canada; Institut Universitaire de France, Paris 75005, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris 75015, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou 215163, China; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 171 76, Sweden
Manal O. Elnenaei: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 4R2, Canada
Shashi A. Gujar: Department of Pathology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada; Department of Biology, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 1X5, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 4R2, Canada; Corresponding author Shashi Gujar, Departments of Pathology, Microbiology & Immunology, Dalhousie University, Rm. 11J Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5, Canada.

Journal volume & issue: Vol. 24
pp. 695 – 706

Abstract

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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.

Published in Molecular Therapy: Oncolytics

ISSN: 2372-7705 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.cell.com/molecular-therapy-family/oncolytics/latest-content

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