Caspase‐8 in Apoptosis: The Beginning of “The End”?

Kruidering, Marieke; Evan, Gérard I.

doi:10.1080/713803693

Cited by 230 publications

(64 citation statements)

References 49 publications

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“…Activated caspase-8 amplifies the apoptotic signal either by directly activating downstream caspases or by cleaving proteins such as Bid [39]. The resulting tBid translocates to the mitochondria from the cytosol to induce mitochondrial damage, cell shrinkage, nuclear condensation and release of cytochrome c [40].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia inhibits TRAIL-induced tumor cell apoptosis: Involvement of lysosomal cathepsins

2006

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Tumor hypoxia interferes with the efficacy of chemotherapy, radiotherapy, and tumor necrosis factor-alpha. TRAIL (tumor necrosis factor-related apoptosis inducing ligand) is a potent apoptosis inducer that limits tumor growth without damaging normal cells and tissues in vivo. We present evidence for a central role of lysosomal cathepsins in hypoxia and/or TRAIL-induced cell death in oral squamous cell carcinoma (OSCC) cells. Hypoxia or TRAIL-induced activation of cathepsins (B, D and L), caspases (-3 and -9), Bid cleavage, release of Bax and cytochrome c, and DNA fragmentation were blocked independently by zVAD-fmk, CA074Me or pepstatin A, consistent with the involvement of lysosomal cathepsin B and D in cell death. Lysosome stability and mitochondrial membrane potential were reduced in hypoxia and TRAIL-induced apoptosis. However, TRAIL treatment under hypoxic condition resulted in diminished apoptosis rates compared to treatment under normoxia. This inhibitory effect of hypoxia on TRAIL-induced apoptosis may be based on preventing Bax activation and thus protecting mitochondria stability. Our data show that TRAIL or hypoxia independently triggered activation of cathepsin B and D leading to apoptosis through Bid and Bax, and suggest that hypoxic tissue regions provide a selective environment for highly apoptosis-resistant clonal cells. Molecular therapy approaches based on cathepsin inhibitors need to address this novel tumor-preventing function of cathepsins in OSCC.

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Section: Discussionmentioning

confidence: 99%

Hypoxia inhibits TRAIL-induced tumor cell apoptosis: Involvement of lysosomal cathepsins

2006

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“…Molecular weight is shown in kDa on the right b other phenotypes [27]. Furthermore, the loss of Caspase 8 is associated with several types of brain cancer including neuroblastomas, medulloblastomas, and glioblastomas [28][29][30]. A better understanding of the inter-relationship between Rybp, Hippi, and Caspase 8 will allow us to ask whether they functionally interact in promoting apoptosis during neural tube formation or other aspects of brain/ neuronal development.…”

Section: Discussionmentioning

confidence: 97%

Rybp interacts with Hippi and enhances Hippi-mediated apoptosis

et al. 2007

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Rybp (DEDAF) has been shown to interact with DED-containing proteins and to encode pro-apoptotic functions. Here we characterize a novel interaction between Rybp and Hippi, a protein implicated in neuronal apoptosis as well as in the pathogenesis of Huntington's disease. Rybp can synergize with Hippi to enhance Caspase 8-mediated apoptosis and also appears to be essential for Hippi-mediated apoptosis. Moreover, Rybp may mediate or regulate the interaction between Hippi and Caspase 8. Finally, Rybp and Hippi co-localize in a subset of neurons in the developing mouse brain. Together, these findings suggest that Rybp and Hippi may functionally interact in the apoptotic processes that accompany normal murine neural development.

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“…The functional mechanism of caspase-2-induced apoptosis remains largely unknown. Caspase-8 is a major activator of caspase-3 and amplifies the apoptotic signal by directly activating downstream caspases and cleaving BH3 domain-only proteins, such as Bid [32,34]. Bid activation is through cleavage by caspase-8, which generates the truncated form, t-Bid [32].…”

Section: Discussionmentioning

confidence: 99%

Sequential caspase-2 and caspase-8 activation is essential for saikosaponin a-induced apoptosis of human colon carcinoma cell lines

Kim

Hong

2010

Apoptosis

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In this study, we investigated the signaling pathways implicated in SSa-induced apoptosis of human colon carcinoma (HCC) cell lines. SSa-induced apoptosis of HCC cells was associated with proteolytic activation of caspase-9, caspase-3, and PARP cleavages and decreased levels of IAP family members, such as XIAP and c-IAP-2, but not of survivin. The fluorescence intensity of DiOC6 was significantly reduced after SSa treatment. CsA significantly inhibited SSa-induced loss of mitochondrial transmembrane potential and moderately inhibited SSa-induced cell death. SSa treatment also enhanced the activities of caspase-2 and caspase-8, Bid cleavage, and the conformational activation of Bax. Additionally, SSa-induced apoptosis was inhibited by both the selective caspase-2 inhibitor z-VDVAD-fmk and the selective caspase-8 inhibitor z-IETD-fmk and also by si-RNAs against caspase-2 and caspase-8. The selective caspase-9 inhibitor, z-LEHD-fmk, also inhibited SSa-induced apoptosis, albeit to a lesser extent compared to z-VDVAD-fmk and z-IETD-fmk, indicating that both mitochondria-dependent and mitochondria-independent pathways are associated with SSa-induced apoptosis. Both z-VDVAD-fmk and z-IETD-fmk significantly attenuated the colony-inhibiting effect of SSa. Moreover, inhibition of caspase-2 activation by the pharmacological inhibitor z-VDVAD-fmk, or by knockdown of protein levels using a si-RNA, suppressed SSa-induced caspase-8 activation, Bid cleavage, and the conformational activation of Bax. Although caspase-8 is an initiator caspase like caspase-2, the inhibition of caspase-8 activation by knockdown using a si-RNA did not suppress SSa-induced caspase-2 activation. Altogether, our results suggest that sequential activation of caspase-2 and caspase-8 is a critical step in SSa-induced apoptosis.

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Caspase‐8 in Apoptosis: The Beginning of “The End”?

Cited by 230 publications

References 49 publications

Hypoxia inhibits TRAIL-induced tumor cell apoptosis: Involvement of lysosomal cathepsins

Hypoxia inhibits TRAIL-induced tumor cell apoptosis: Involvement of lysosomal cathepsins

Rybp interacts with Hippi and enhances Hippi-mediated apoptosis

Sequential caspase-2 and caspase-8 activation is essential for saikosaponin a-induced apoptosis of human colon carcinoma cell lines

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