Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death Journal Article

   

Authors:	Graham, N. A.; Tahmasian, M.; Kohli, B.; Komisopoulou, E.; Zhu, M.; Vivanco, I.; Teitell, M. A.; Wu, H.; Ribas, A.; Lo, R. S.; Mellinghoff, I. K.; Mischel, P. S.; Graeber, T. G.
Article Title:	Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death
Abstract:	The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis. © 2012 EMBO and Macmillan Publishers Limited. All rights reserved.
Keywords:	signal transduction; controlled study; protein expression; human cell; genetics; neoplasm; neoplasms; mass spectrometry; metabolism; cell death; cell viability; cell survival; biological model; models, biological; phosphatase; cancer cell culture; pathology; cell line, tumor; protein tyrosine kinase; proteomics; physiology; cancer cell; tumor cell line; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; reactive oxygen species; reactive oxygen metabolite; glucose; protein-tyrosine kinases; oxidative stress; feedback system; molecular interaction; protein tyrosine phosphatase; pten protein, mouse; mitochondria; feedback, physiological; cell metabolism; mitochondrion; phosphotyrosine; nadph oxidase; focal adhesion; focal adhesions; protein tyrosine phosphatases; oxidation reduction state; reduced nicotinamide adenine dinucleotide phosphate oxidase
Journal Title:	Molecular Systems Biology
Volume:	8
ISSN:	1744-4292
Publisher:	Nature Publishing Group
Date Published:	2012-06-24
Start Page:	589
Language:	English
DOI:	10.1038/msb.2012.20
PROVIDER:	scopus
PMCID:	PMC3397414
PUBMED:	22735335
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84863337299&partnerID=40&md5=349ffe28879f8808a4624fcbd3c9126a
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 1 August 2012" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/31874