Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide- and etoposide-induced apoptosis

Chiou Feng Lin, Chia-Ling Chen, Wen-Tsan Chang, Ming-Shiou Jan, Li-Jin Hsu, Ren-Huang Wu, Ming-Jer Tang, Wen Chang Chang, Yee-Shin Lin

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111 Citations (Scopus)


Recently, caspase-2 was shown to act upstream of mitochondria in stress-induced apoptosis. Activation of caspase-8, a key event in death receptor-mediated apoptosis, also has been demonstrated in death receptor-independent apoptosis. The regulation of these initiator caspases, which trigger the mitochondrial apoptotic pathway, is unclear. Here we report a potential regulatory role of caspase-2 on caspase-8 during ceramide-induced apoptosis. Our results demonstrate the sequential events of initiator caspase-2 and caspase-8 activation, Bid cleavage and translocation, and mitochondrial damage followed by downstream caspase-9 and -3 activation and cell apoptosis after ceramide induction in T cell lines. The expression of truncated Bid (tBid) and the reduction in mitochondrial transmembrane potential were blocked by caspase-2 or caspase-8, but not caspase-3, knockdown using an RNA interference technique. Ceramide-induced caspase-8 activation, mitochondrial damage, and apoptosis were blocked in caspase-2 short interfering RNA-expressing cells. Therefore, caspase-2 acts upstream of caspase-8 during ceramide-induced mitochondrial apoptosis. Similarly, sequential caspase-2 and caspase-8 activation upstream of mitochondria was also observed in etoposide-induced apoptosis. These data suggest sequential initiator caspase-2 and caspase-8 activation in the mitochondrial apoptotic pathway induced by ceramide or etoposide.

Original languageEnglish
Pages (from-to)40755-40761
Number of pages7
JournalJournal of Biological Chemistry
Issue number39
Publication statusPublished - Sep 24 2004

ASJC Scopus subject areas

  • Biochemistry


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