Ruefli A A, Ausserlechner M J, Bernhard D, Sutton V R, Tainton K M, Kofler R, Smyth M J, Johnstone R W
Cancer Immunology Division, The Peter MacCallum Cancer Institute, Trescowthick Research Laboratories, Saint Andrews Place, East Melbourne, Victoria 3002, Australia.
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10833-8. doi: 10.1073/pnas.191208598. Epub 2001 Sep 4.
Many chemotherapeutic agents induce mitochondrial-membrane disruption to initiate apoptosis. However, the upstream events leading to drug-induced mitochondrial perturbation have remained poorly defined. We have used a variety of physiological and pharmacological inhibitors of distinct apoptotic pathways to analyze the manner by which suberoylanilide hydroxamic acid (SAHA), a chemotherapeutic agent and histone deacetylase inhibitor, induces cell death. We demonstrate that SAHA initiates cell death by inducing mitochondria-mediated death pathways characterized by cytochrome c release and the production of reactive oxygen species, and does not require the activation of key caspases such as caspase-8 or -3. We provide evidence that mitochondrial disruption is achieved by means of the cleavage of the BH3-only proapoptotic Bcl-2 family member Bid. SAHA-induced Bid cleavage was not blocked by caspase inhibitors or the overexpression of Bcl-2 but did require the transcriptional regulatory activity of SAHA. These data provide evidence of a mechanism of cell death mediated by transcriptional events that result in the cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death.
许多化疗药物会诱导线粒体膜破坏以引发细胞凋亡。然而，导致药物诱导的线粒体扰动的上游事件仍不清楚。我们使用了多种不同凋亡途径的生理和药理抑制剂，来分析一种化疗药物兼组蛋白脱乙酰酶抑制剂——辛二酰苯胺异羟肟酸（SAHA）诱导细胞死亡的方式。我们证明，SAHA通过诱导线粒体介导的死亡途径引发细胞死亡，其特征为细胞色素c释放和活性氧的产生，并且不需要关键半胱天冬酶如半胱天冬酶-8或-3的激活。我们提供的证据表明，线粒体破坏是通过仅含BH3结构域的促凋亡Bcl-2家族成员Bid的裂解来实现的。SAHA诱导的Bid裂解不受半胱天冬酶抑制剂或Bcl-2过表达的阻断，但确实需要SAHA的转录调节活性。这些数据提供了一种由转录事件介导的细胞死亡机制的证据，这些转录事件导致Bid裂解、线粒体膜破坏和活性氧产生，从而诱导细胞死亡。
