Ischemia in Tumors Induces Early and Sustained Phosphorylation Changes in Stress Kinase Pathways but Does Not Affect Global Protein Levels

作者：Philipp Mertins, Feng Qiu Yang, Tao Liu, D.R. Mani, Vladislav Petyuk, Michael A. Gillette, Karl R. Clauser, Jana Qiao, Marina A. Gritsenko, Ronald Jay Moore, Douglas A. Levine, Reid Townsend, Petra Erdmann-Gilmore, Jacqueline Snider, Sherri R. Davies, Kelly V. Ruggles, David Fenyö, RT Kitchens, Shunqiang Li, Narciso Olvera, Fanny Dao, Henry Rodriguez, Daniel W. Chan, Daniel C. Liebler, Forest M. White, Karin Rodland, Gordon Brent Mills, Richard Smith, Amanda G. Paulovich, Matthew J. Ellis, Steven A. Carr · 发表于：Molecular & Cellular Proteomics · 年份：2014 · DOI：10.1074/mcp.m113.036392 · 被引用次数：429 · 研究领域：Cancer, Hypoxia, and Metabolism、Mitochondrial Function and Pathology、Melanoma and MAPK Pathways

Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. Although the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 min, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation, and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples and motivates reexamination of collection protocols for phosphoprotein analysis.