Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness
Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness
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DOI：
10.1073/pnas.162187599
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发表时间：
2002-08-06
影响因子：
11.1
通讯作者：
Cravatt, BF
中科院分区：
文献类型：
--
作者：
Jessani, N;Liu, YS;Cravatt, BF
通过主要测量转录物和蛋白质丰度的变化，传统的基因组学和蛋白质组学方法可能无法检测调节蛋白质活性并最终调节细胞行为的重要翻译后事件。为了解决这些限制，在全球范围内测量蛋白质功能动态的基于活性的蛋白质组技术将具有特别的价值。在这里，我们描述了化学蛋白质组学策略的应用，以定量比较一组人类乳腺癌和黑色素瘤癌细胞系的酶活性。对丝氨酸水解酶超家族的活性、亚细胞分布和糖基化状态的全局分析导致鉴定出一组蛋白酶、脂肪酶和酯酶，这些酶可根据组织来源区分癌细胞系。引人注目的是，在所检查的最具侵袭性的癌细胞系中，几乎所有这些酶活性均被下调，相反，一组独特的分泌酶和膜相关酶活性上调。这些与侵袭性相关的酶包括尿激酶（一种在肿瘤进展中具有公认作用的分泌性丝氨酸蛋白酶）和膜相关水解酶 KIAA1363（之前尚未将其与癌症联系起来）。总的来说，这些结果表明，侵袭性癌细胞共享离散的蛋白质组特征，这些特征比细胞遗传更能反映其生物表型，强调一组共同的酶可能支持多种起源的肿瘤的进展，因此代表了癌症诊断和治疗的有吸引力的靶标。
By primarily measuring changes in transcript and protein abundance, conventional genomics and proteomics methods may fail to detect significant posttranslational events that regulate protein activity and, ultimately, cell behavior. To address these limitations, activity-based proteomic technologies that measure dynamics in protein function on a global scale would be of particular value. Here, we describe the application of a chemical proteomics strategy to quantitatively compare enzyme activities across a panel of human breast and melanoma cancer cell lines. A global analysis of the activity, subcellular distribution, and glycosylation state for the serine hydrolase superfamily resulted in the identification of a cluster of proteases, lipases, and esterases that distinguished cancer lines based on tissue of origin. Strikingly, nearly all of these enzyme activities were down-regulated in the most invasive cancer lines examined, which instead up-regulated a distinct set of secreted and membrane-associated enzyme activities. These invasiveness-associated enzymes included urokinase, a secreted serine protease with a recognized role in tumor progression, and a membrane-associated hydrolase KIAA1363, for which no previous link to cancer had been made. Collectively, these results suggest that invasive cancer cells share discrete proteomic signatures that are more reflective of their biological phenotype than cellular heritage, highlighting that a common set of enzymes may support the progression of tumors from a variety of origins and thus represent attractive targets for the diagnosis and treatment of cancer.