Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells

Elena Favaro; Karim Bensaad; Mei G. Chong; Daniel A. Tennant; David J.P. Ferguson; Cameron Snell; Graham Steers; Helen Turley; Ji Liang Li; Ulrich L. Günther; Francesca M. Buffa; Alan McIntyre; Adrian L. Harris

doi:10.1016/j.cmet.2012.10.017

Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells

Elena Favaro, Karim Bensaad, Mei G. Chong, Daniel A. Tennant, David J.P. Ferguson, Cameron Snell, Graham Steers, Helen Turley, Ji Liang Li, Ulrich L. Günther, Francesca M. Buffa, Alan McIntyre, Adrian L. Harris^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Chemie und Metabolomics

351 Zitate (Scopus)

Abstract

Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.

Originalsprache	Englisch
Zeitschrift	Cell Metabolism
Jahrgang	16
Ausgabenummer	6
Seiten (von - bis)	751-764
Seitenumfang	14
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2012.10.017
Publikationsstatus	Veröffentlicht - 05.12.2012

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The authors would like to thank Hocine W. Mankouri for helpful discussion and critical review of the manuscript. The authors are grateful to Stefano Indraccolo for providing samples of the Her-2/neu transgenic mouse model. This study was supported by GlaxoSmithKline, the University of Oxford, CRUK, the EU 6th and 7th Framework Programs, the Breast Cancer Research Foundation, the Oxford National Institute for Health Research Comprehensive Biomedical Research, the Oxford CRUK Cancer Centre, and the EU METAFLUX grant.

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Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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10.1016/j.cmet.2012.10.017

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Favaro, E., Bensaad, K., Chong, M. G., Tennant, D. A., Ferguson, D. J. P., Snell, C., Steers, G., Turley, H., Li, J. L., Günther, U. L., Buffa, F. M., McIntyre, A., & Harris, A. L. (2012). Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metabolism, 16(6), 751-764. https://doi.org/10.1016/j.cmet.2012.10.017

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title = "Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells",

abstract = "Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.",

author = "Elena Favaro and Karim Bensaad and Chong, \{Mei G.\} and Tennant, \{Daniel A.\} and Ferguson, \{David J.P.\} and Cameron Snell and Graham Steers and Helen Turley and Li, \{Ji Liang\} and G{\"u}nther, \{Ulrich L.\} and Buffa, \{Francesca M.\} and Alan McIntyre and Harris, \{Adrian L.\}",

note = "Funding Information: The authors would like to thank Hocine W. Mankouri for helpful discussion and critical review of the manuscript. The authors are grateful to Stefano Indraccolo for providing samples of the Her-2/neu transgenic mouse model. This study was supported by GlaxoSmithKline, the University of Oxford, CRUK, the EU 6th and 7th Framework Programs, the Breast Cancer Research Foundation, the Oxford National Institute for Health Research Comprehensive Biomedical Research, the Oxford CRUK Cancer Centre, and the EU METAFLUX grant. Copyright: Copyright 2013 Elsevier B.V., All rights reserved.",

year = "2012",

month = dec,

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doi = "10.1016/j.cmet.2012.10.017",

language = "English",

volume = "16",

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T1 - Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells

AU - Favaro, Elena

AU - Bensaad, Karim

AU - Chong, Mei G.

AU - Tennant, Daniel A.

AU - Ferguson, David J.P.

AU - Snell, Cameron

AU - Steers, Graham

AU - Turley, Helen

AU - Li, Ji Liang

AU - Günther, Ulrich L.

AU - Buffa, Francesca M.

AU - McIntyre, Alan

AU - Harris, Adrian L.

N1 - Funding Information: The authors would like to thank Hocine W. Mankouri for helpful discussion and critical review of the manuscript. The authors are grateful to Stefano Indraccolo for providing samples of the Her-2/neu transgenic mouse model. This study was supported by GlaxoSmithKline, the University of Oxford, CRUK, the EU 6th and 7th Framework Programs, the Breast Cancer Research Foundation, the Oxford National Institute for Health Research Comprehensive Biomedical Research, the Oxford CRUK Cancer Centre, and the EU METAFLUX grant. Copyright: Copyright 2013 Elsevier B.V., All rights reserved.

PY - 2012/12/5

Y1 - 2012/12/5

N2 - Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.

AB - Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation.

UR - https://www.scopus.com/pages/publications/84870507227

U2 - 10.1016/j.cmet.2012.10.017

DO - 10.1016/j.cmet.2012.10.017

M3 - Journal articles

C2 - 23177934

AN - SCOPUS:84870507227

SN - 1550-4131

VL - 16

SP - 751

EP - 764

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells

Abstract

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