Cell Metabolism Previews Linking Glycogen and Senescence in Cancer Cells Susana Ros1 and Almut Schulze1,* 1Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2012.11.010 Glycogen metabolism operates as an alternative energy source, enabling cell growth under conditions of metabolic stress. Favaro et al. (2012) now demonstrate that in hypoxic cancer cells, depletion of liver glycogen phosphorylase causes glycogen accumulation, leading to oxidative stress, induction of senes- cence, and impaired tumor growth in vivo. Among the various metabolic adaptations (PYGL) was previously found among the the survival of cancer cells (Figure 1). employed by cancer cells to adjust to the 99 genes included in a hypoxia ‘‘meta- Based on this model, PYGL silencing conditions imposed by the tumor micro- gene’’ signature, which predicts poor impairs glycogen breakdown, results in environment, changes in glycogen meta- survival in head and neck squamous cell decreased flux through the PPP, and bolism are emerging as an essential carcinomas and breast cancer (Winter diminishes NADPH levels, which not only response (Brahimi-Horn et al., 2011). et al., 2007). Therefore, the role of provide the reductive power for the Understanding the role of glycogen glycogen degradation in response to synthesis of macromolecules for cell metabolism in neoplastic transformation hypoxia and in cancer cell survival re- growth and proliferation, but also main- requires a better knowledge of how this mained unclear. tain cellular redox balance. The increase metabolic pathway is regulated in cancer. To address this question, Favaro et al. in reactive oxygen species (ROS) after Favaro et al. now demonstrate that inhibi- examined xenografts of U87 glioblastoma silencing of PYGL leads to p53 activation tion of glycogen mobilization in cancer cells in mice treated with the antiangio- and induction of senescence. In agree- cells leads to the induction of senes- genic drug bevacizumab. They found ment with this conclusion, Favaro et al. cence and impairs tumor growth (Favaro that hypoxic areas in the treated tumors found that induction of senescence was et al., 2012). expressed both GYS1 and PYGL and partially reversed by cosilencing of p53 Hypoxia is an important component of showed marked accumulation of gly- or treatment with a ROS scavenger. the tumor microenvironment and regu- cogen. Consistent with this finding, they However, it cannot be excluded that the lates several processes essential for observed an acute induction of GYS1 hyperaccumulation of glycogen itself has tumor formation. Hypoxia promotes the expression and glycogen accumulation an effect on cellular signaling processes storage of glucose in the form of glycogen in several cancer cell lines (U87 glioblas- and contributes to the induction of senes- in nonmalignant as well as in cancer cells toma, MCF-7 breast cancer, and HCT- cence. Evidence for this comes from the for later use under more drastic, nutrient- 116 colon cancer cells) exposed to cosilencing of glycogen synthase, which limiting conditions (Brahimi-Horn et al., hypoxia. PYGL mRNA levels, on the other resulted in diminished glycogen stores 2011). A previous study showed that hand, increased only after longer expo- and rescued the senescence phenotype. nonmalignant cells exposed to low sure to hypoxia and correlated with Several published observations reinforce oxygen induce the expression of GYS1, a reduction in glycogen content, suggest- this concept. The b1 subunit of AMPK the muscle isoform of glycogen synthase ing activation of glycogen breakdown contains a glycogen-binding site, and (the key enzyme involved in glycogen during the later stages of the hypoxia AMPK is believed to be in its active state synthesis), using a mechanism depen- response. Indeed, PYGL expression was when glycogen particles are fully synthe- dent on the hypoxia-inducible factor elevated in several different tumor types, sized. Persistent activation of AMPK can (HIF) (Pescador et al., 2010). However, relative to normal tissues. Importantly, lead to the induction of p53-dependent the activity of glycogen phosphorylase silencing of PYGL, by siRNA, in different cellular senescence (Jones et al., 2005). (the key enzyme involved in glycogen cancer cell lines led to increased Furthermore, sublethal doses of inhibitors degradation) was decreased (Pescador glycogen content and resulted in induc- of glycogen synthase kinase 3 (GSK-3), et al., 2010). Parallel findings were re- tion of senescence, both in normoxia one of the kinases that regulates glycogen ported in human MCF-7 breast cancer and hypoxia, although the increase in synthesis through phosphorylation and cells (Shen et al., 2010). In this system, glycogen stores was more prominent in inhibition of glycogen synthase, have short-term hypoxia led to glycogen accu- low oxygen. Remarkably, PYGL silencing also been reported to induce cellular mulation by the HIF-dependent induction by shRNA strongly impaired the growth senescence accompanied by enhanced of protein phosphatase 1 regulatory of the U87 xenograft cells. glycogenesis and increased glycogen subunit 3C (PPP1R3C or PTG). This acti- To explain these findings, Favaro et al. content (Seo et al., 2008). vated glycogen synthase and decreased propose a model in which channeling of Previous studies suggested that short- glycogen phosphorylase activity (Shen glucose-6-phosphate toward the pentose term hypoxia promotes accumulation of et al., 2010). On the other hand, the liver phosphate pathway (PPP), caused by glycogen by increasing glycogen syn- isoform of glycogen phosphorylase glycogen mobilization, is essential for thase activity while decreasing the activity Cell Metabolism 16, December 5, 2012 ª2012 Elsevier Inc. 687 Cell Metabolism Previews players involved in glycogen metabolism that can be considered as targets for future anticancer therapies. The study by Favaro et al. highlights glycogen metabolism as a promising metabolic Achilles’ heel for cancer treat- ment. Moreover, glycogen mobilization could allow cancer cells to bypass limita- tions in nutrient supply caused by antian- giogenic drugs, making it an attractive target for combination therapies. This study paves the way for a better under- standing of the regulation of this impor- tant metabolic pathway in cancer. Figure 1. Overview of Glycogen Metabolism in Cancer Cells Exposed to Hypoxia and Effects REFERENCES of PYGL Depletion Favaro et al. report the induction of several enzymes involved in glycogen synthesis (blue) and degradation 10 (red) in cancer cells under hypoxic conditions. Channeling of glucose through glycogen promotes the Agius, L. (2010). Mini Rev. Med. Chem. , 1175– survival of cancer cells under hypoxia. Depletion of PYGL reduces glycogen mobilization and impairs 1187. NADPH production due to decreased flux through the PPP, resulting in ROS accumulation and induction Brahimi-Horn, M.C., Bellot, G., and Pouysse´ gur, J. of senescence. Branching enzyme 1, GBE1; glucose transporter 1, GLUT1; glycogen phosphorylase liver (2011). Curr. Opin. Genet. Dev. 21, 67–72. isoform, PYGL; glycogen synthase muscle isoform, GYS1; glucose-1-phosphate, Glc-1-P; glucose-6- phosphate, Glc-6-P; hexokinase II, HK-II; phosphoglucomutase 1, PGM-1; pentose phosphate pathway, Camus, S., Quevedo, C., Mene´ ndez, S., Paramo- PPP; reactive oxygen species, ROS; UDP-glucose, UDP-Glc. nov, I., Stouten, P.F., Janssen, R.A., Rueb, S., He, S., Snaar-Jagalska, B.E., Laricchia-Robbio, L., and Izpisua Belmonte, J.C. (2012). Oncogene of glycogen phosphorylase (Shen et al., cancer. However, it is important to 31, 4333–4342. 2010). The results of Favaro et al. now consider that the phosphorylated (active) Favaro, E., Bensaad, K., Chong, M.G., Tennant, also implicate glycogen mobilization in form of PYGL is a potent allosteric inhib- D.A., Ferguson, D.J.P., Snell, C., Steers, G., Turley, H., Li, J.-L., Gu¨ nther, U.L., et al. (2012). Cell Metab. the late response of cancer cells to itor of protein phosphatase-1 (PP1), which 16, this issue, 751–764. hypoxia. The late induction of PYGL may dephosphorylates and activates glycogen reflect the temporally dynamic nature of synthase (Agius, 2010). PYGL inhibition Jones, K.R., Elmore, L.W., Jackson-Cook, C., Demasters, G., Povirk, L.F., Holt, S.E., and Ge- glycogen metabolism within the hypoxia could thus not only prevent glycogen wirtz, D.A. (2005). Int. J. Radiat. Biol. 81, 445–458. response. This could be particularly degradation but also promote its syn- Pelletier, J., Bellot, G., Gounon, P., Lacas-Gervais, important in the context of fluctuating thesis, thereby further limiting the flux of S., Pouysse´ gur, J., and Mazure, N.M. (2012). Front. nutrient and oxygen availability within glucose-6-phosphate toward the PPP Oncol. 2, 18. the tumor microenvironment. (Figure 1). Indeed, other proteins involved Pescador, N., Villar, D., Cifuentes, D., Garcia- These findings suggest that PYGL may in glycogen metabolism, some of them Rocha, M., Ortiz-Barahona, A., Vazquez, S., represent a target for anticancer therapy. being regulated by HIF, have been already Ordon˜ ez, A., Cuevas, Y., Saez-Morales, D., 5 Drug discovery programs are already proposed as therapeutic targets (Pelletier Garcia-Bermejo, M.L., et al. (2010). PLoS ONE , e9644. exploring PYGL as a therapeutic target et al., 2012; Pescador et al., 2010). for the treatment of type 2 diabetes,