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.
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Favaro
authors.forename: Karim
authors.initials: K
authors.lastname: Bensaad
authors.forename: Mei G
authors.initials: MG
authors.lastname: Chong
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Tennant
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.forename: Cameron
authors.initials: C
authors.lastname: Snell
authors.forename: Graham
authors.initials: G
authors.lastname: Steers
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Ulrich L
authors.initials: UL
authors.lastname: Günther
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000068258:Bevacizumab; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D005947:Glucose