Abstract
Cancer cells exhibit a unique metabolic shift to aerobic glycolysis that has been exploited diagnostically and therapeutically in the clinic. Oncogenes and tumor suppressors alter signaling pathways that lead to alterations of glycolytic flux. Stemming from glycolysis, the hexosamine biosynthetic pathway leads to elevated posttranslational addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) on a diverse population of nuclear and cytosolic proteins, many of which regulate signaling pathways. This unit outlines techniques used to detect metabolic alterations in cancer cells, regulation by signaling pathways, and cellular O-GlcNAcylation.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsSpringer Nature is developing a new tool to find and evaluate Protocols. Learn more
References
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:19345–19350
Wellen KE, Thompson CB (2010) Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell 40:323–332
Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022
Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, Vosseller K, Reginato MJ (2010) Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29:2831–2842
Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ (2012) Critical role of O-Linked beta-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem 287:11070–11081
Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, Peters EC, Driggers EM, Hsieh-Wilson LC (2012) Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337:975–980
Itkonen HM, Minner S, Guldvik IJ, Sandmann MJ, Tsourlakis MC, Berge V, Svindland A, Schlomm T, Mills IG (2013) O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer. Cancer Res 73(16):5277–5287
Shaw RJ, Cantley LC (2012) Decoding key nodes in the metabolism of cancer cells: sugar & spice and all things nice. F1000 Biol Rep 4:2
Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35
Semenza GL (2011) Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 76:347–353
Whelan KA, Schwab LP, Karakashev SV, Franchetti L, Johannes GJ, Seagroves TN, Reginato MJ (2013) The oncogene HER2/neu (ERBB2) requires the hypoxia-inducible factor HIF-1 for mammary tumor growth and anoikis resistance. J Biol Chem 288:15865–15877
Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J, Muthuswamy SK, Brugge JS (2003) Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 5:733–740
Tandon P, Gallo CA, Khatri S, Barger JF, Yepiskoposyan H, Plas DR (2011) Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. Proc Natl Acad Sci U S A 108:2361–2365
Li L, Zhang L, Zhang X, Yan Q, Minamishima YA, Olumi AF, Mao M, Bartz S, Kaelin WG Jr (2007) Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol 27:5381–5392
Debnath J, Muthuswamy SK, Brugge JS (2003) Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30:256–268
Semenza GL (2011) Oxygen sensing, homeostasis, and disease. N Engl J Med 365:537–547
Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47
Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51–56
Whelan KA, Caldwell SA, Shahriari KS, Jackson SR, Franchetti LD, Johannes GJ, Reginato MJ (2010) Hypoxia suppression of Bim and Bmf blocks anoikis and luminal clearing during mammary morphogenesis. Mol Biol Cell 21:3829–3837
Yang X, Su K, Roos MD, Chang Q, Paterson AJ, Kudlow JE (2001) O-linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc Natl Acad Sci U S A 98:6611–6616
Zachara NE (2009) Detecting the “O-GlcNAc-ome”; detection, purification, and analysis of O-GlcNAc modified proteins. Methods Mol Biol 534:251–279
Acknowledgements
We acknowledge Valerie L. Sodi for critical reading of this chapter. We thank previous members of Reginato lab for establishing some of these protocols. This work was supported in part by NIH-NCI grant RO1CA155413.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Ferrer, C.M., Reginato, M.J. (2014). Cancer Metabolism: Cross Talk Between Signaling and O-GlcNAcylation. In: Wajapeyee, N. (eds) Cancer Genomics and Proteomics. Methods in Molecular Biology, vol 1176. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0992-6_7
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0992-6_7
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-0991-9
Online ISBN: 978-1-4939-0992-6
eBook Packages: Springer Protocols