Dissecting DISC regulation via pharmacological targeting of caspase-8/c-FLIPL heterodimer

Hillert, Laura K.; Ivanisenko, Nikita V.; Busse, Denise; Espe, Johannes; König, Corinna; Peltek, S. E.; Колчанов, Н. А.; Иванисенко, В. А.; Lavrik, Inna N.

doi:10.1038/s41418-020-0489-0

Cited by 20 publications

(23 citation statements)

References 40 publications

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“…This proapoptotic activity is dependent on caspase-8 and negatively regulated by elevated c-FLIP levels. This further underlines the importance of compounds reducing c-FLIP levels, as promising agents against SARS-CoV-2 along with the compounds activating caspase-8 52,53 . Interestingly, c-FLIP has been recently shown to protect macrophages from LPS-induced pyroptosis via inhibition of complex II formation; thus, playing a dual role in pyroptosis and apoptosis regulation 72 .…”

Section: Targeting Dd-mediated Network At the Later Stages Of Sars-cmentioning

confidence: 71%

“…Therefore, inducing extrinsic apoptosis and caspase-8 activation via targeting c-FLIP or caspase-8 at the beginning of the infection seems to be an important strategy to inhibit virus replication, and limit the number of viruses. In this regard, recent reports on small molecules activating caspase-8 via targeting caspase-8/c-FLIP L heterodimers, or small molecules activating caspase-8 at the initial steps after death ligand administration might be of particular interest 52 (Fig. 2).…”

Section: Targeting Extrinsic Cell Death As a Strategy To Combat Sars-mentioning

confidence: 99%

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The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications

et al. 2020

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The current pandemic of novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) poses a significant global public health threat. While urgent regulatory measures in control of the rapid spread of this virus are essential, scientists around the world have quickly engaged in this battle by studying the molecular mechanisms and searching for effective therapeutic strategies against this deadly disease. At present, the exact mechanisms of programmed cell death upon SARS-CoV-2 infection remain to be elucidated, though there is increasing evidence suggesting that cell death pathways play a key role in SARS-CoV-2 infection. There are several types of programmed cell death, including apoptosis, pyroptosis, and necroptosis. These distinct programs are largely controlled by the proteins of the death domain (DD) superfamily, which play an important role in viral pathogenesis and host antiviral response. Many viruses have acquired the capability to subvert the program of cell death and evade the host immune response, mainly by virally encoded gene products that control cell signaling networks. In this mini-review, we will focus on SARS-CoV-2, and discuss the implication of restraining the DD-mediated signaling network to potentially suppress viral replication and reduce tissue damage.

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Section: Targeting Dd-mediated Network At the Later Stages Of Sars-cmentioning

confidence: 71%

Section: Targeting Extrinsic Cell Death As a Strategy To Combat Sars-mentioning

confidence: 99%

The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications

et al. 2020

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“…However, in most of the previous studies this involves the non-specific www.nature.com/scientificreports/ downregulation of c-FLIP and Mcl-1, which has a number of disadvantages. In our study we used the first-in-class chemical probe targeting c-FLIP L and the specific inhibitor of Mcl-1, which makes our approach more specific 25 . The future studies aimed on improving the structure of FLIPinB should allow to further increase the effects of this combinatorial treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Upon high concentrations of c-FLIP L , it plays only an anti-apoptotic role because high amounts of c-FLIP L in the DED filaments downmodulates caspase-8 activation 19 . To specifically enhance pro-apoptotic effects of the caspase-8/c-FLIP L heterodimer in cancer cells we have rationally designed the small molecule termed FLIPinB/FLIPinBγ targeting caspase-8-p43/c-FLIP L heterodimer, the processed form of procaspase-8/c-FLIP L heterodimer 25 . FLIPinB/FLIPinBγ binds at the interface of caspase-8/c-FLIP L heterodimer and enhances its catalytic activity and thereby CD95L/TRAIL-induced cell death (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological targeting of c-FLIPL and Bcl-2 family members promotes apoptosis in CD95L-resistant cells

König

Hillert-Richter

Ivanisenko

et al. 2020

Sci Rep

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The development of efficient combinatorial treatments is one of the key tasks in modern anti-cancer therapies. An apoptotic signal can either be induced by activation of death receptors (DR) (extrinsic pathway) or via the mitochondria (intrinsic pathway). Cancer cells are characterized by deregulation of both pathways. Procaspase-8 activation in extrinsic apoptosis is controlled by c-FLIP proteins. We have recently reported the small molecules FLIPinB/FLIPinBγ targeting c-FLIPL in the caspase-8/c-FLIPL heterodimer. These small molecules enhanced caspase-8 activity in the death-inducing signaling complex (DISC), CD95L/TRAIL-induced caspase-3/7 activation and subsequent apoptosis. In this study to increase the pro-apoptotic effects of FLIPinB/FLIPinBγ and enhance its therapeutic potential we investigated costimulatory effects of FLIPinB/FLIPinBγ in combination with the pharmacological inhibitors of the anti-apoptotic Bcl-2 family members such as ABT-263 and S63845. The combination of these inhibitors together with FLIPinB/FLIPinBγ increased CD95L-induced cell viability loss, caspase activation and apoptosis. Taken together, our study suggests new approaches for the development of combinatorial anti-cancer therapies specifically targeting both intrinsic and extrinsic apoptosis pathways.

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Core Models of Receptor Reactions to Evaluate Basic Pathway Designs Enabling Heterogeneous Commitments to Apoptosis

Péré

Chaves

Roux

2020

Computational Methods in Systems Biology

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Isogenic cells can respond differently to cytotoxic drugs, such as the tumor necrosis factor-related apoptosis inducing ligand (TRAIL), with only a fraction committing to apoptosis. Since non-genetic transient resistance to TRAIL has been shown to dependent on caspase-8 dynamics at the receptor level in vitro, here we investigate the core reactions leading to caspase-8 activation, based on mass-action kinetics models, to evaluate the basic mechanisms giving rise to the observed heterogeneous response. In this work, we fit our models to single-cell trajectories of time-resolved caspase-8 activation measured in clonal cells after treatment with TRAIL. Then, we analyse our results to assess the relevance of each model and evaluate how well it captures the extent of biological heterogeneity observed in vitro. Particularly, we focus on a positive feedback loop on caspase-8, the impacts of initial condition variations and the relevance of the caspase-8 degradation.

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Dissecting DISC regulation via pharmacological targeting of caspase-8/c-FLIPL heterodimer

Cited by 20 publications

References 40 publications

The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications

The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications

Pharmacological targeting of c-FLIPL and Bcl-2 family members promotes apoptosis in CD95L-resistant cells

Core Models of Receptor Reactions to Evaluate Basic Pathway Designs Enabling Heterogeneous Commitments to Apoptosis

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