Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94114, USA.
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12432-7. doi: 10.1073/pnas.1208616109. Epub 2012 Jul 16.
Proapoptotic drugs are a mainstay of cancer drug treatment. These drugs stress cells and ultimately trigger the activation of caspases, cysteine-class proteases that cleave after aspartic acid and deconstruct the cell. It is well known that cells respond differently to proapoptotic cancer drug treatments. Here, using a global and unbiased quantitative N-terminomics technology, we show that ~500 products of caspase cleavage and their kinetics vary dramatically between cell type and cytotoxic drug treatment. It is likely that variations arise from differences in baseline proteome composition of the cell type and the alterations induced by drug treatments to yield a unique cohort of proteins that caspases finally target. Many targets are specific to both drug treatment and cell type, providing candidate-specific biomarkers for apoptosis. For example, in multiple myeloma cells treated with the proteasome inhibitor bortezomib, levels of activating transcription factor-4 increase dramatically early in drug treatment and then decrease upon cleavage by activated caspases. Thus, caspase-derived cleavage products are a sensitive reflection of cell-type and drug-induced stress, and provide useful fingerprints for mechanisms of drug action and response.
促凋亡药物是癌症药物治疗的主要手段。这些药物对细胞施加压力，最终触发半胱天冬酶（caspase）的激活，半胱天冬酶是天冬氨酸后切割的胱氨酸蛋白酶家族，可破坏细胞。众所周知，细胞对促凋亡癌症药物治疗的反应不同。在这里，我们使用一种全局且无偏的定量 N 端组学技术，表明在细胞类型和细胞毒性药物治疗之间，有约 500 种半胱天冬酶切割产物及其动力学存在显著差异。这些差异可能源于细胞类型的基线蛋白质组组成的差异以及药物治疗引起的变化，从而产生半胱天冬酶最终靶向的独特蛋白群。许多靶点对药物治疗和细胞类型都具有特异性，为细胞凋亡提供了候选特异性生物标志物。例如，在多发性骨髓瘤细胞中用蛋白酶体抑制剂硼替佐米（ bortezomib ）治疗时，激活转录因子 4 的水平在药物治疗早期急剧增加，然后在被激活的半胱天冬酶切割时降低。因此，半胱天冬酶衍生的切割产物是细胞类型和药物诱导应激的敏感反映，并为药物作用和反应机制提供了有用的指纹。
