文章：

诊断和利用癌症对细胞凋亡的依赖性

Diagnosing and exploiting cancer's addiction to blocks in apoptosis

原文发布日期：2008-02-01

DOI: 10.1038/nrc2297

类型: Review Article

开放获取: 否

要点：

1. Cancer cells exhibit many phenotypes, such as genomic instability or oncogene activation, that ought to induce apoptosis, but they nonetheless survive. A block in apoptosis is a likely requirement for cancer maintenance.
2. In cancer cells that overexpress BCL2 the protein itself is often largely bound to pro-apoptotic BH3-only proteins like BIM. In such circumstances we describe BCL2 and the cell as being 'primed'.
3. BH3 profiling is a novel tool that exploits selective interaction between BH3 domains and anti-apoptotic BCL2 proteins to reveal the different ways cancer cells escape apoptosis. Certain cancer cells escape apoptosis by expression of BCL2; BH3 profiling can specifically identify these primed, BCL2-dependent cells.
4. BCL2 expression does not necessarily confer a chemoresistant phenotype to cancer cells when selected for in previously untreated cells. If the expressed BCL2 is primed, sequestering large amounts of pro-apoptotic proteins such as BIM, it may actually relate to increased chemosensitivity.
5. Primed cells are selectively sensitive to antagonists of anti-apoptotic BCL2 proteins like ABT-737. Primed cells might also be selectively more sensitive to conventional chemotherapy agents compared with cancer cells that use a different apoptotic block.
6. It has long been suspected that cancer cells are more susceptible to cell death than normal cells. That some cancer cells appear to be primed for death in comparison with normal cells offers a possible biochemical explanation for this clinical observation.
7. Small-molecule drugs that target BCL2 and related anti-apoptotic proteins are currently in early-phase clinical trials.

要点翻译：

1. 癌细胞表现出许多本应诱导凋亡的表型，如基因组不稳定性或癌基因激活，但它们却能够存活。凋亡阻断很可能是维持癌症状态的必要条件。
2. 在过度表达BCL2的癌细胞中，该蛋白本身常大量与促凋亡的仅含BH3结构域蛋白（如BIM）结合。此类情况下，我们称BCL2及细胞处于"待发状态"。
3. BH3谱分析是一种新型工具，它利用BH3结构域与抗凋亡BCL2蛋白之间的选择性相互作用，揭示癌细胞逃逸凋亡的不同机制。某些癌细胞通过表达BCL2来逃逸凋亡；BH3谱分析能特异性识别这些处于待发状态、依赖BCL2的细胞。
4. 在未经治疗的细胞中被选择性表达时，BCL2的表达并不必然赋予癌细胞化疗耐药表型。若表达的BCL2处于待发状态（即隔离大量促凋亡蛋白如BIM），反而可能与增加的化疗敏感性相关。
5. 处于待发状态的细胞对ABT-737等抗凋亡BCL2蛋白拮抗剂具有选择性敏感。与采用不同凋亡阻断机制的癌细胞相比，待发状态细胞对传统化疗药物可能也更具选择性敏感。
6. 长期以来学界推测癌细胞比正常细胞更易发生细胞死亡。某些癌细胞相较于正常细胞呈现"待发死亡"状态，这一发现为该临床观察提供了可能的生化解释。
7. 靶向BCL2及相关抗凋亡蛋白的小分子药物目前正处于早期临床试验阶段。

英文摘要：

Cancer cells survive despite violating rules of normal cellular behaviour that ordinarily provoke apoptosis. The blocks in apoptosis that keep cancer cells alive are therefore attractive candidates for targeted therapies. Recent studies have significantly increased our understanding of how interactions among proteins in the BCL2 family determine cell survival or death. It is now possible to systematically determine how individual cancers escape apoptosis. Such a determination can help predict not only whether cells are likely to be killed by antagonism of BCL2, but also whether they are likely to be sensitive to chemotherapy that kills by the intrinsic apoptotic pathway.

摘要翻译： 

尽管癌细胞违反了通常会引发凋亡的正常细胞行为规则，它们仍能存活。因此，阻断凋亡、使癌细胞得以存活的机制成为靶向治疗的热门候选。近期研究显著加深了我们对BCL2家族蛋白间相互作用如何决定细胞存活或死亡的理解。如今，我们已能系统性地明确个别癌症如何逃避凋亡。此类判断不仅有助于预测细胞是否可能因拮抗BCL2而被杀死，还可预测其是否可能对通过内在凋亡通路发挥作用的化疗药物敏感。

原文链接：

Diagnosing and exploiting cancer's addiction to blocks in apoptosis