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.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…Glycogen synthesis and the pentose phosphate pathway are upregulated in tumor cells subjected to hypoxia. 116 Thus, in response to ischemia, in which Akt activity and mitoHK-II are decreased (resulting in increased cytosolic HK-II), HK-II would stimulate these cytosolic events to preserve cellular homeostasis. (4) As discussed later, non-mitochondrial HK-II facilitates autophagy induced by glucose withdrawal, 117 suggesting regulation of energy conservation by HK-II.…”

Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods

“…Inhibition of glycogen phosphorylase (GP), the main regulatory enzyme of glycogen metabolism, has been connected to type 2 diabetes mellitus, [2][3][4][5] and during the last decade also to other diseased states such as myocardial 6,7 and cerebral 8,9 ischemia as well as tumors [10][11][12][13] as amply discussed in recent reviews and primary research articles. Liver and muscle isoforms of GP have been thoroughly characterized, the structural features of the proteins and the binding sites are well known and have been surveyed, 14,15 therefore these enzymes are ideal targets for rational and structure-based inhibitor design.…”

Homeostasis and the glycogen shunt explains aerobic ethanol production in yeast

“…Due to similarities of yeast and cancer cells, the glycogen shunt observed in yeast could play a similar mechanistic role for maintaining homeostasis in cancer cells exposed to changes in substrate. There are a number of papers that have shown that glycogen is important for cancer cell growth (5,45). Schwartz et al, in 1975 (46), reported the time course of the disappearance of a 5-mM glucose load followed by the lagging formation and disappearance of glycogen in a suspension of C-6 glioma cells.…”

“…He proposed that now we must seek an understanding of the reciprocity between the regulatory state driven by signals from transcription factors and the dynamics of metabolic control. This was a timely call because the interactions of genetics and metabolism, developed in yeast research (2), was becoming paradigmatic in cancer studies (3)(4)(5). Because both cancer cells and yeast derive metabolites and energy from glucose, the relations of yeast metabolism with genetic expression, rather well understood in the glucose pathways, are providing an informative parallel for the study of cancer cells (6,7).…”