School of Biological Sciences, Cancer and Stem Cell Biology Group, University of Essex, Colchester CO4 3SQ, UK.
National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland.
Cell Death Differ. 2018 Feb;25(2):340-352. doi: 10.1038/cdd.2017.164. Epub 2017 Nov 3.
The mechanisms of how chemotherapeutic drugs lead to cell cycle checkpoint regulation and DNA damage repair are well understood, but how such signals are transmitted to the cellular apoptosis machinery is less clear. We identified a novel apoptosis-inducing complex, we termed FADDosome, which is driven by ATR-dependent caspase-10 upregulation. During FADDosome-induced apoptosis, cFLIP is ubiquitinated by TRAF2, leading to its degradation and subsequent FADD-dependent caspase-8 activation. Cancer cells lacking caspase-10, TRAF2 or ATR switch from this cell-autonomous suicide to a more effective, autocrine/paracrine mode of apoptosis initiated by a different complex, the FLIPosome. It leads to processing of cFLIP to cFLIP, TNF-α production and consequently, contrary to the FADDosome, p53-independent apoptosis. Thus, targeting the molecular levers that switch between these mechanisms can increase efficacy of treatment and overcome resistance in cancer cells.
化疗药物如何导致细胞周期检查点调节和 DNA 损伤修复的机制已被充分理解，但这些信号如何传递到细胞凋亡机制尚不清楚。我们鉴定了一种新的凋亡诱导复合物，我们称之为 FADDosome，它是由 ATR 依赖性 caspase-10 上调驱动的。在 FADDosome 诱导的凋亡过程中，cFLIP 被 TRAF2 泛素化，导致其降解，随后 FADD 依赖性 caspase-8 激活。缺乏 caspase-10、TRAF2 或 ATR 的癌细胞会从这种自主自杀切换到一种更有效的、由另一种复合物（FLIPosome）起始的、自分泌/旁分泌的凋亡模式。它导致 cFLIP 向 cFLIP 的加工、TNF-α 的产生，并且与 FADDosome 相反，p53 非依赖性凋亡。因此，靶向这些机制之间转换的分子杠杆可以提高治疗效果并克服癌细胞的耐药性。
