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^*

^*Corresponding author for this work

Institute of Chemistry and Metabolomics

335 Citations (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.

Original language	English
Journal	Cell Metabolism
Volume	16
Issue number	6
Pages (from-to)	751-764
Number of pages	14
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2012.10.017
Publication status	Published - 05.12.2012

Funding

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.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2012.10.017

Cite this

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.",

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

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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.

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

Abstract

Funding

Research Areas and Centers

UN SDGs

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