Caspase-8 is a cysteine - aspartate specific protease that classically triggers the extrinsic apoptotic pathway, in response to the activation of cell surface Death Receptors (DRs) like FAS, TRAIL-R and TNF-R. Besides it's roles in triggering death receptor-mediated apoptosis, Caspase-8 has also been implicated in the onsets of anoikis, autophagy and pyroptosis. Furthermore, Caspase-8 also plays a crucial pro-survival function by inhibiting an alternative form of programmed cell death called necroptosis. Low expression levels of pro-Caspase-8 is therefore associated with the malignant transformation of cancers. However, the long-held notion that pro-Caspase-8 expression/activity is generally lost in most cancers, thereby contributing to apoptotic escape and enhanced resistance to anti-cancer therapeutics, has been found to be true for only a minority of cancers types. In the majority of cases, pro-Caspase-8 expression is maintained and sometimes elevated, while it's apoptotic activity is regulated through different mechanisms. This supports the notion that the non-apoptotic functions of Caspase-8 offer growth advantage in these cancer types and have, therefore, gained renewed interest in the recent years. In light of these reasons, a number of therapeutic approaches have been employed, with the intent of targeting pro-Caspase-8 in cancer cells. In this review, we would attempt to discuss - the classic roles of Caspase-8 in initiating apoptosis; it's non-apoptotic functions; it's the clinical significance in different cancer types; and the therapeutic applications exploiting the ability of pro-Caspase-8 to regulate various cellular functions.

中文翻译：

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Caspase-8：双刃剑。

Caspase-8是一种半胱氨酸-天冬氨酸特异性蛋白酶，通常会触发FAS，TRAIL-R和TNF-R等细胞表面死亡受体（DR）的活化，从而触发外在凋亡途径。除了其在触发死亡受体介导的细胞凋亡中的作用外，Caspase-8还参与了神经衰弱，自噬和发烧的发作。此外，Caspase-8还通过抑制编程性细胞死亡的另一种形式称为坏死性坏死发挥重要的促生存功能。因此，前胱天蛋白酶8的低表达水平与癌症的恶性转化有关。但是，长期存在的观念认为，Caspase-8的表达/活性在大多数癌症中通常会丢失，从而导致凋亡逃逸并增强了对抗癌疗法的抵抗力，已经发现只有少数几种癌症是正确的。在大多数情况下，前胱天蛋白酶8的表达得以维持，有时甚至升高，而其凋亡活性则通过不同的机制进行调节。这支持了以下观点：Caspase-8的非凋亡功能在这些癌症类型中提供了生长优势，因此近年来获得了新的关注。鉴于这些原因，已经采用了许多治疗方法，目的是靶向癌细胞中的前胱天蛋白酶8。在这篇综述中，我们将尝试讨论-Caspase-8在启动细胞凋亡中的经典作用；它是非凋亡功能；在不同类型的癌症中具有临床意义；