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

doi:10.1016/j.omto.2022.02.017

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

Medicine

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

6 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	695-706
Número de páginas	12
Publicación	Molecular Therapy - Oncolytics
Volumen	24
DOI	https://doi.org/10.1016/j.omto.2022.02.017
Estado	Published - mar. 17 2022

Nota bibliográfica

Funding Information:
This work was supported by the Dalhousie Medical Research Foundation (DMRF), Canadian Institutes of Health Research (CIHR), Cancer Research Society (CRS), and Beatrice Hunter Cancer Research Institute (BHCRI) to S.G. B.E.K. J.P.M. and M.G. are funded by BHCRI's Cancer Research Training Program (CRTP). B.E.K is also funded by Dalhousie Medical Research Foundation (DMRF)/Infection, Immunity, Inflammation & Vaccinology (I3V). P.K. is funded by Nova Scotia Graduate Scholarship (NSGS). We would like to thank Drs. Alejandro Cohen (Dalhousie University) and Sylvere Durand (Gustave Roussy) for their expertise with metabolomics and mass spectrometry. The graphical abstract was created with BioRender.com. Finally, we thank the Dalhousie University animal care facility and staff for general maintenance of all animals used in this study. Conception and design: B.E. Kennedy and S. Gujar. Development of methodology: B.E. Kennedy, M. Giacomantonio, J.P. Murphy, S. Cutler, P. Konda, S. Cutler, J.A. Paulo, and D. Gaston. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): B.E. Kennedy, M. Giacomantonio, J.P. Murphy, S. Cutler, M. Sadek, J.A. Paulo, G.P. Pathak, S. Renkens, S. Grieve, A. Cohen, J. Pol, G. Kroemer, S.P. Gygi, C. Richardson, M.O. Elnenaei, D. Gaston, T. Reiman, and S. Gujar. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): B.E. Kennedy, J.P. Murphy, P. Konda, M. Giacomantonio, S. Cutler, and J.A. Paulo. Writing, review, and/or revision of the manuscript: B.E. Kennedy, J.P. Murphy, M. Giacomantonio, S. Cutler, M. Sadek, and S. Gujar. Administrative, technical, or material support (i.e. reporting or organizing data, constructing databases): B.E. Kennedy, J.P. Murphy, and S. Gujar. Study supervision: S. Gujar. Other (funding): S. Gujar. The authors declare that they have no conflict of interest or competing financial interests.

Funding Information:
This work was supported by the Dalhousie Medical Research Foundation (DMRF), Canadian Institutes of Health Research (CIHR), Cancer Research Society (CRS), and Beatrice Hunter Cancer Research Institute (BHCRI) to S.G. B.E.K., J.P.M., and M.G. are funded by BHCRI’s Cancer Research Training Program (CRTP). B.E.K is also funded by Dalhousie Medical Research Foundation (DMRF)/Infection, Immunity, Inflammation & Vaccinology (I3V). P.K. is funded by Nova Scotia Graduate Scholarship (NSGS). We would like to thank Drs. Alejandro Cohen (Dalhousie University) and Sylvere Durand (Gustave Roussy) for their expertise with metabolomics and mass spectrometry. The graphical abstract was created with BioRender.com . Finally, we thank the Dalhousie University animal care facility and staff for general maintenance of all animals used in this study.

Publisher Copyright:
© 2022 The Authors

ASJC Scopus Subject Areas

Molecular Medicine
Oncology
Cancer Research
Pharmacology (medical)

PubMed: MeSH publication types

Journal Article

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Acceder al documento

10.1016/j.omto.2022.02.017

Otros archivos y enlaces

Citar esto

Kennedy, B. E., Giacomantonio, M., Murphy, J. P., Cutler, S., Sadek, M., Konda, P., Paulo, J. A., Pathak, G. P., Renkens, S. H. J., Grieve, S., Pol, J., Gygi, S. P., Richardson, C., Gaston, D., Reiman, A., Kroemer, G., Elnenaei, M. O., & Gujar, S. A. (2022). NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma. Molecular Therapy - Oncolytics, 24, 695-706. https://doi.org/10.1016/j.omto.2022.02.017

Kennedy, BE, Giacomantonio, M, Murphy, JP, Cutler, S, Sadek, M, Konda, P, Paulo, JA, Pathak, GP, Renkens, SHJ, Grieve, S, Pol, J, Gygi, SP, Richardson, C , Gaston, D, Reiman, A, Kroemer, G, Elnenaei, MO & Gujar, SA 2022, 'NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma', Molecular Therapy - Oncolytics, vol. 24, pp. 695-706. https://doi.org/10.1016/j.omto.2022.02.017

@article{a4fd1b9890b3448388e26fa7fa5bcc35,

title = "NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma",

abstract = "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.",

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

note = "Funding Information: This work was supported by the Dalhousie Medical Research Foundation (DMRF), Canadian Institutes of Health Research (CIHR), Cancer Research Society (CRS), and Beatrice Hunter Cancer Research Institute (BHCRI) to S.G. B.E.K. J.P.M. and M.G. are funded by BHCRI's Cancer Research Training Program (CRTP). B.E.K is also funded by Dalhousie Medical Research Foundation (DMRF)/Infection, Immunity, Inflammation & Vaccinology (I3V). P.K. is funded by Nova Scotia Graduate Scholarship (NSGS). We would like to thank Drs. Alejandro Cohen (Dalhousie University) and Sylvere Durand (Gustave Roussy) for their expertise with metabolomics and mass spectrometry. The graphical abstract was created with BioRender.com. Finally, we thank the Dalhousie University animal care facility and staff for general maintenance of all animals used in this study. Conception and design: B.E. Kennedy and S. Gujar. Development of methodology: B.E. Kennedy, M. Giacomantonio, J.P. Murphy, S. Cutler, P. Konda, S. Cutler, J.A. Paulo, and D. Gaston. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): B.E. Kennedy, M. Giacomantonio, J.P. Murphy, S. Cutler, M. Sadek, J.A. Paulo, G.P. Pathak, S. Renkens, S. Grieve, A. Cohen, J. Pol, G. Kroemer, S.P. Gygi, C. Richardson, M.O. Elnenaei, D. Gaston, T. Reiman, and S. Gujar. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): B.E. Kennedy, J.P. Murphy, P. Konda, M. Giacomantonio, S. Cutler, and J.A. Paulo. Writing, review, and/or revision of the manuscript: B.E. Kennedy, J.P. Murphy, M. Giacomantonio, S. Cutler, M. Sadek, and S. Gujar. Administrative, technical, or material support (i.e. reporting or organizing data, constructing databases): B.E. Kennedy, J.P. Murphy, and S. Gujar. Study supervision: S. Gujar. Other (funding): S. Gujar. The authors declare that they have no conflict of interest or competing financial interests. Funding Information: This work was supported by the Dalhousie Medical Research Foundation (DMRF), Canadian Institutes of Health Research (CIHR), Cancer Research Society (CRS), and Beatrice Hunter Cancer Research Institute (BHCRI) to S.G. B.E.K., J.P.M., and M.G. are funded by BHCRI{\textquoteright}s Cancer Research Training Program (CRTP). B.E.K is also funded by Dalhousie Medical Research Foundation (DMRF)/Infection, Immunity, Inflammation & Vaccinology (I3V). P.K. is funded by Nova Scotia Graduate Scholarship (NSGS). We would like to thank Drs. Alejandro Cohen (Dalhousie University) and Sylvere Durand (Gustave Roussy) for their expertise with metabolomics and mass spectrometry. The graphical abstract was created with BioRender.com . Finally, we thank the Dalhousie University animal care facility and staff for general maintenance of all animals used in this study. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = mar,

day = "17",

doi = "10.1016/j.omto.2022.02.017",

language = "English",

volume = "24",

pages = "695--706",

journal = "Molecular Therapy - Oncolytics",

issn = "2372-7705",

publisher = "Cell Press",

}

TY - JOUR

T1 - NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma

AU - Kennedy, Barry E.

AU - Giacomantonio, Michael

AU - Murphy, J. Patrick

AU - Cutler, Samuel

AU - Sadek, Maryanne

AU - Konda, Prathyusha

AU - Paulo, Joao A.

AU - Pathak, Gopal P.

AU - Renkens, Saskia H.J.

AU - Grieve, Stacy

AU - Pol, Jonathan

AU - Gygi, Steven P.

AU - Richardson, Christopher

AU - Gaston, Daniel

AU - Reiman, Anthony

AU - Kroemer, Guido

AU - Elnenaei, Manal O.

AU - Gujar, Shashi A.

N1 - Funding Information: This work was supported by the Dalhousie Medical Research Foundation (DMRF), Canadian Institutes of Health Research (CIHR), Cancer Research Society (CRS), and Beatrice Hunter Cancer Research Institute (BHCRI) to S.G. B.E.K. J.P.M. and M.G. are funded by BHCRI's Cancer Research Training Program (CRTP). B.E.K is also funded by Dalhousie Medical Research Foundation (DMRF)/Infection, Immunity, Inflammation & Vaccinology (I3V). P.K. is funded by Nova Scotia Graduate Scholarship (NSGS). We would like to thank Drs. Alejandro Cohen (Dalhousie University) and Sylvere Durand (Gustave Roussy) for their expertise with metabolomics and mass spectrometry. The graphical abstract was created with BioRender.com. Finally, we thank the Dalhousie University animal care facility and staff for general maintenance of all animals used in this study. Conception and design: B.E. Kennedy and S. Gujar. Development of methodology: B.E. Kennedy, M. Giacomantonio, J.P. Murphy, S. Cutler, P. Konda, S. Cutler, J.A. Paulo, and D. Gaston. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): B.E. Kennedy, M. Giacomantonio, J.P. Murphy, S. Cutler, M. Sadek, J.A. Paulo, G.P. Pathak, S. Renkens, S. Grieve, A. Cohen, J. Pol, G. Kroemer, S.P. Gygi, C. Richardson, M.O. Elnenaei, D. Gaston, T. Reiman, and S. Gujar. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): B.E. Kennedy, J.P. Murphy, P. Konda, M. Giacomantonio, S. Cutler, and J.A. Paulo. Writing, review, and/or revision of the manuscript: B.E. Kennedy, J.P. Murphy, M. Giacomantonio, S. Cutler, M. Sadek, and S. Gujar. Administrative, technical, or material support (i.e. reporting or organizing data, constructing databases): B.E. Kennedy, J.P. Murphy, and S. Gujar. Study supervision: S. Gujar. Other (funding): S. Gujar. The authors declare that they have no conflict of interest or competing financial interests. Funding Information: This work was supported by the Dalhousie Medical Research Foundation (DMRF), Canadian Institutes of Health Research (CIHR), Cancer Research Society (CRS), and Beatrice Hunter Cancer Research Institute (BHCRI) to S.G. B.E.K., J.P.M., and M.G. are funded by BHCRI’s Cancer Research Training Program (CRTP). B.E.K is also funded by Dalhousie Medical Research Foundation (DMRF)/Infection, Immunity, Inflammation & Vaccinology (I3V). P.K. is funded by Nova Scotia Graduate Scholarship (NSGS). We would like to thank Drs. Alejandro Cohen (Dalhousie University) and Sylvere Durand (Gustave Roussy) for their expertise with metabolomics and mass spectrometry. The graphical abstract was created with BioRender.com . Finally, we thank the Dalhousie University animal care facility and staff for general maintenance of all animals used in this study. Publisher Copyright: © 2022 The Authors

PY - 2022/3/17

Y1 - 2022/3/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85125657438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85125657438&partnerID=8YFLogxK

U2 - 10.1016/j.omto.2022.02.017

DO - 10.1016/j.omto.2022.02.017

M3 - Article

C2 - 35284625

AN - SCOPUS:85125657438

SN - 2372-7705

VL - 24

SP - 695

EP - 706

JO - Molecular Therapy - Oncolytics

JF - Molecular Therapy - Oncolytics

ER -

NAD+ depletion enhances reovirus-induced oncolysis in multiple myeloma

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODS de las Naciones Unidas

Acceder al documento

Otros archivos y enlaces

Huella

Citar esto