Ischemia in Tumors Induces Early and Sustained Phosphorylation Changes in Stress Kinase Pathways but Does Not Affect Global Protein Levels
Ischemia in Tumors Induces Early and Sustained Phosphorylation Changes in Stress Kinase Pathways but Does Not Affect Global Protein Levels
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DOI：
10.1074/mcp.m113.036392
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发表时间：
2014-07-01
影响因子：
7
通讯作者：
Carr, Steven A.
中科院分区：
文献类型：
--
作者：
Mertins, Philipp;Yang, Feng;Carr, Steven A.
蛋白质丰度和磷酸化传达了关于包括癌症在内的疾病中的通路活性和分子病理生理学的重要信息，提供了生物学见解，为药物和诊断开发提供了信息，并指导了治疗干预。分析的组织通常是在没有严格规定或记录缺血时间的情况下收集的。为了评估缺血的影响，我们收集了人卵巢肿瘤和乳腺癌异种移植组织，没有血管中断，并进行定量蛋白质组学和磷酸化蛋白质组学确定的缺血间隔后。尽管总体表达的蛋白质组和> 25，000个定量磷酸化位点中的大多数在60分钟后没有变化，但在高达24%的磷酸化蛋白质组中观察到快速磷酸化变化，这代表与应激反应、转录调节和细胞死亡相关的关键癌症途径的激活。观察到泛肿瘤和组织特异性变化。分析前组织缺血对肿瘤生物学的影响已得到证实，因此在解释此类样本中的应激途径激活时应谨慎，并促使重新检查磷蛋白分析的收集方案。
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.