Caspase-8: The double-edged sword

Mandal, Ranadip; Compte, Joan; Kostova, Izabela; Becker, Sven; Strebhardt, Klaus

doi:10.1016/j.bbcan.2020.188357

Cited by 105 publications

(85 citation statements)

References 232 publications

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“…Pro-caspase-8a differs from pro-caspase-8b by a longer linker between the prodomain and catalytic domain ( Fig. 1a) [14]. The activation of pro-caspase-8a/b occurs after the formation of the death-inducing signaling complex (DISC).…”

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

“…Cleaved Bid migrates from the cytosol to the outer mitochondrial membrane and interacts with Bax and Bak. This complex allows release of cytochrome c and the activation of Apaf1/caspase 9 apoptosome [19] heterodimer: p18 2 -p10 2 [14]. The programmed cell death, mediated by caspase-8, is regulated by several mechanisms [15].…”

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

“…Low levels of cFLIP L enhance apoptosis, whereas high levels inhibit caspase-8. In contrast, cFLIP short (cFLIP S ) blocks the recruitment of caspase-8 to the DISC and prevents the oligomerization of p18 and p10 [14,15].…”

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

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The role of caspase-8 in the tumor microenvironment of ovarian cancer

Kostova

Mandal

Becker

et al. 2020

Cancer Metastasis Rev

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Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.

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Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

Section: Apoptotic and Non-apoptotic Functions Of Caspase-8mentioning

confidence: 99%

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The role of caspase-8 in the tumor microenvironment of ovarian cancer

Kostova

Mandal

Becker

et al. 2020

Cancer Metastasis Rev

Self Cite

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“…In the canonical pathway, upon ligand binding, the death domain recruits adaptor proteins, also containing a death domain sequence, forming a signaling complex with pro-caspase 8, resulting in its activation or repression. This initiator caspase, in turn, activates the executioner caspases (see review by Mandal et al, 2020). However, the complexity of this route is much greater.…”

Section: Apoptosis Activated By the Extrinsic Pathwaymentioning

confidence: 99%

“…On the one hand, many members of the signaling cascade perform developmental functions other than promoting cell death (Sessler et al, 2013). On the other hand, two other initiator caspases, Caspase 10 and Caspase 2 may also participate in the signaling pathway and, most importantly, the extrinsic pathway may switch to other routes of cell death, including necroptosis and apoptosis via the intrinsic pathway (Mandal et al, 2020).…”

Section: Apoptosis Activated By the Extrinsic Pathwaymentioning

confidence: 99%

Confluence of Cellular Degradation Pathways During Interdigital Tissue Remodeling in Embryonic Tetrapods

Montero

Lorda‐Diez

Hurlé

2020

Front. Cell Dev. Biol.

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Digits develop in the distal part of the embryonic limb primordium as radial prechondrogenic condensations separated by undifferentiated mesoderm. In a short time interval the interdigital mesoderm undergoes massive degeneration to determine the formation of free digits. This fascinating process has often been considered as an altruistic cell suicide that is evolutionarily-regulated in species with different degrees of digit webbing. Initial descriptions of interdigit remodeling considered lysosomes as the primary cause of the degenerative process. However, the functional significance of lysosomes lost interest among researcher and was displaced to a secondary role because the introduction of the term apoptosis. Accumulating evidence in recent decades has revealed that, far from being a unique method of embryonic cell death, apoptosis is only one among several redundant dying mechanisms accounting for the elimination of tissues during embryonic development. Developmental cell senescence has emerged in the last decade as a primary factor implicated in interdigit remodeling. Our review proposes that cell senescence is the biological process identified by vital staining in embryonic models and implicates lysosomes in programmed cell death. We review major structural changes associated with interdigit remodeling that may be driven by cell senescence. Furthermore, the identification of cell senescence lacking tissue degeneration, associated with the maturation of the digit tendons at the same stages of interdigital remodeling, allowed us to distinguish between two functionally distinct types of embryonic cell senescence, "constructive" and "destructive."

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Synthesis and antitumor potential of new arylidene ursolic acid derivatives via caspase‐8 activation

Zhu

Chen

et al. 2021

Archiv der Pharmazie

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Continuing our studies on NO-donating ursolic acid-benzylidene derivatives as potential antitumor agents, we designed and synthesized a series of new arylidene derivatives containing NO-donating ursolic acid and aromatic heterocyclic units.Compounds 5c and 6c showed a significant broad-spectrum antitumor activity.Compound 5c exhibited nearly three-to nine-fold higher cytotoxicity as compared with the parent drug in A549, MCF-7, HepG-2, HT-29, and HeLa cells, and it was also found to be the most potent apoptosis inducer of MCF-7 cells. More importantly, compound 5c arrested the MCF-7 cell cycle in the G1 phase, which was associated with caspase activation and a decrease of the Bcl-2/Bax ratio. Meanwhile, compound 5c caused changes in morphological features, dissipation of the mitochondrial membrane potential, and accumulation of reactive oxygen species. A docking study revealed that the nitroxyethyl moiety of compound 5c may form hydrogen bonds with caspase-8 amino acid residues (SER256 and HIS255). Together, these data suggest that NO-donating ursolic acid-arylidene derivatives are potent apoptosis inducers in tumor cells.antitumor activity, apoptosis inducer, NO donor prodrug, ursolic acid derivatives | INTRODUCTIONApoptosis (also called programmed cell death) was described to perform various functions in development. [1] It plays an important role not only in embryogenesis but also in the regulation of cell numbers and the elimination of unwanted cells. The previous literature pointed out that irregularity in apoptosis may cause a number of human diseases, such as neurodegenerative disorders, immunodeficiency, AIDS, and cancer. [2][3][4] Subsequent studies confirmed that apoptosis is one of the major pathways involved in the proliferation, migration, and invasion of tumor cells. Most of the cytotoxic compounds were reported to induce apoptosis in cancer cells. The developments of apoptosis inducers have become effective methods for cancer therapy. [5,6] In general, there is a balance between apoptosis and proliferation in normal cells. [7] The balance depends on the Bcl-2/Bax ratio. It is worth noting that high levels of Bcl-2/Bax ratio may increase the risk of cancer. An excess of Bcl-2 promotes migration and invasion of tumor cells. [8] Morphological alterations, including cell shrinkage, chromatin condensation, and nuclear fragmentation, are important features of tumor cell apoptosis. [9] It has been proved that most of the morphological changes are caused by caspase family proteases. Caspases are divided into three subfamilies, I (caspase-2, -8, -9, and -10),

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Caspase-8: The double-edged sword

Cited by 105 publications

References 232 publications

The role of caspase-8 in the tumor microenvironment of ovarian cancer

The role of caspase-8 in the tumor microenvironment of ovarian cancer

Confluence of Cellular Degradation Pathways During Interdigital Tissue Remodeling in Embryonic Tetrapods

Synthesis and antitumor potential of new arylidene ursolic acid derivatives via caspase‐8 activation

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