期刊
MOLECULAR SYSTEMS BIOLOGY
卷 8, 期 -, 页码 -出版社
WILEY
DOI: 10.1038/msb.2012.20
关键词
cancer; metabolism; phosphatase; proteomics; reactive oxygen species
资金
- UCLA Scholars in Oncologic Molecular Imaging (SOMI) program
- NIH [R25T CA098010]
- UCLA Tumor Biology Program United States Health and Human Services Ruth L. Kirschstein Institutional National Research Service [T32 CA009056]
- Jonsson Comprehensive Cancer Center (JCCC)
- California Institute of Technology-University of California, Los Angeles Joint Center for Translational Medicine (JCTM)
- National Institutes of Health [CA-16042, AI-28697]
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
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. Molecular Systems Biology 8: 589; published online 26 June 2012; doi:10.1038/msb.2012.20
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据