Caspase-8 Induces Lysosome-Associated Cell Death in Cancer Cells

作者：Benfu Zhong, Miao Liu, Changsen Bai, Yuxia Ruan, Yuanyuan Wang, Qiu Li, Yang Hong, Xin Wang, Lifang Li, Binghui Li · 发表于：Molecular Therapy · 年份：2020 · DOI：10.1016/j.ymthe.2020.01.022 · 被引用次数：49 · 研究领域：Cell death mechanisms and regulation、Autophagy in Disease and Therapy、PARP inhibition in cancer therapy

Caspase-8, a well-characterized initiator of apoptosis, has also been found to play non-apoptotic roles in cells. In this study, we reveal that caspase-8 can induce cell death in a special way, which does not depend on activation of caspases and mitochondrial initiation. Instead, we prove that caspase-8 can cause lysosomal deacidification and thus lysosomal membrane permeabilization. V-ATPase is a multi-subunit proton pump that acidifies the lumen of lysosome. Our results demonstrate that caspase-8 can bind to the V 0 domain of lysosomal Vacuolar H + -ATPase (V-ATPase), but not the V 1 domain, to block the assembly of functional V-ATPase and alkalinize lysosomes. We further demonstrate that the C-terminal of caspase-8 is mainly responsible for the interaction with V-ATPase and can suffice to inhibit survival of cancer cells. Interestingly, regardless of the protein level, it is the expression rate of caspase-8 that is the major cause of cell death. Taken together, we identify a previously unrevealed caspase-8-mediated cell death pathway different form typical apoptosis, which could render caspase-8 a particular physiological function and may be potentially applied in treatments for apoptosis-resistant cancers.