Faculty Opinions recommendation of Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.

Abstract 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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Faculty Opinions recommendation of Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1010062.146007 ◽

2002 ◽

Author(s):

Christoph Borner

Keyword(s):

Lymphocyte Activation ◽

Caspase 8

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Faculty Opinions recommendation of Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1010062.142607 ◽

2002 ◽

Author(s):

David Wallach

Keyword(s):

Lymphocyte Activation ◽

Caspase 8

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N-Terminal Fragment of c-FLIP(L) Processed by Caspase 8 Specifically Interacts with TRAF2 and Induces Activation of the NF-κB Signaling Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.24.7.2627-2636.2004 ◽

2004 ◽

Vol 24 (7) ◽

pp. 2627-2636 ◽

Cited By ~ 168

Author(s):

Takao Kataoka ◽

Jürg Tschopp

Keyword(s):

Immune System ◽

Signaling Pathway ◽

Death Receptor ◽

Lymphocyte Activation ◽

Dominant Negative ◽

Caspase 8 ◽

Caspase Inhibitor ◽

Splice Form ◽

Signaling Complex ◽

Terminal Fragment

ABSTRACT Caspase 8 is required not only for death receptor-mediated apoptosis but also for lymphocyte activation in the immune system. FLIP(L), the long-splice form of c-FLIP, is one of the specific substrates for caspase 8, and increased expression of FLIP(L) promotes activation of the NF-κB signaling pathway. The synthetic caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) markedly blocked NF-κB activation induced by overexpression of FLIP(L). FLIP(L) is specifically processed by caspase 8 into N-terminal FLIP(p43) and C-terminal FLIP(p12). Only FLIP(p43) was able to induce NF-κB activation as efficiently as FLIP(L), and FLIP(p43)-induced NF-κB activation became insensitive to zVAD-fmk. In caspase 8-deficient cells, FLIP(p43) provoked NF-κB activation only when procaspase 8 or caspase 8(p43) was complemented. FLIP(p43)-induced NF-κB activation was profoundly blocked by the dominant-negative TRAF2. Moreover, endogenous TRAF2 interacted specifically with FLIP(p43), and the formation of the FLIP(p43)-caspase 8-TRAF2 tertiary complex was a prerequisite to induction of NF-κB activation. zVAD-fmk prevented the recruitment of TRAF2 into the death-inducing signaling complex. Thus, our present results demonstrate that FLIP(p43) processed by caspase 8 specifically interacts with TRAF2 and subsequently induces activation of the NF-κB signaling pathway.

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