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Targeting glycogen metabolism in bladder cancer

Nature Reviews Urology volume 12, pages 383–391 (2015)Cite this article

Subjects

Key Points

  • Aerobic glycolysis (the Warburg effect) has been extensively studied in urological and other cancer models, but changes in other metabolic pathways also warrant investigation

  • Glycogen metabolism is one metabolic pathway that is altered in cancer and is just beginning to be understood

  • Loss of the glycogen debranching enzyme (AGL) leads to increased proliferation of bladder cancer cells in vitro and in vivo, and has prognostic value in patients with bladder cancer

  • Glycogen phosphorylase, involved in glycogen breakdown, is important for cancer cell survival in some tissues

  • Glycogen phosphorylase and metabolic alterations resulting from reduced AGL expression might represent new targets in the treatment of urological cancers

Abstract

Metabolism has been a heavily investigated topic in cancer research for the past decade. Although the role of aerobic glycolysis (the Warburg effect) in cancer has been extensively studied, abnormalities in other metabolic pathways are only just being understood in cancer. One such pathway is glycogen metabolism; its involvement in cancer development, particularly in urothelial malignancies, and possible ways of exploiting aberrations in this process for treatment are currently being studied. New research shows that the glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL) is a novel tumour suppressor in bladder cancer. Loss of AGL leads to rapid proliferation of bladder cancer cells. Another enzyme involved in glycogen debranching, glycogen phosphorylase, has been shown to be a tumour promoter in cancer, including in prostate cancer. Studies demonstrate that bladder cancer cells in which AGL expression is lost are more metabolically active than cells with intact AGL expression, and these cells are more sensitive to inhibition of both glycolysis and glycine synthesis—two targetable pathways. As a tumour promoter and enzyme, glycogen phosphorylase can be directly targeted, and preclinical inhibitor studies are promising. However, few of these glycogen phosphorylase inhibitors have been tested for cancer treatment in the clinical setting. Several possible limitations to the targeting of AGL and glycogen phosphorylase might also exist.

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Figure 1: Glycogen metabolism pathways and drug targets.
Figure 2: Glycogenolysis.
Figure 3: Differences between glycogen phosphorylase and AGL loss in cancer.

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Acknowledgements

Supported in part by National Institutes of Health grant CA143971 to D.T., the Bladder Cancer Advocacy Network (BCAN) Young Investigator Award and the Cancer League of Colorado, Inc. Research Grant to S.G., and the National Institutes of Health Ruth L. Kirschstein F32 National Research Service Award (NRSA) F32CA189735 to C.R.L.

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  1. Department of Surgery (Urology), University of Colorado, 12700 East 19th Avenue, RC2/P15-6430D/MS-8609, Aurora, 80045, CO, USA

    Carolyn Ritterson Lew & Sunny Guin

  2. University of Colorado Comprehensive Cancer Center, MS F-434, 13001 East 17th Place, Aurora, 80045, CO, USA

    Dan Theodorescu

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Lew, C., Guin, S. & Theodorescu, D. Targeting glycogen metabolism in bladder cancer. Nat Rev Urol 12, 383–391 (2015). https://doi.org/10.1038/nrurol.2015.111

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