Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28

Müller, Ines; Stróżyk, Elwira; Schindler, Sebastian; Beissert, Stefan; Oo, Htoo Zarni; Sauter, Thomas; Lucarelli, Philippe; Raeth, Sebastian; Haußer, Angelika; Nakouzi, Nader Al; Fazli, Ladan; Gleave, Martin; He, Li; Simon, Hans‐Uwe; Walczak, Henning; Green, Douglas R.; Bártek, Jiří; Daugaard, Mads; Kulms, Dagmar

doi:10.1016/j.molcel.2019.12.023

Cited by 66 publications

(70 citation statements)

References 49 publications

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“…In many tumors with poor prognosis, such as hepatocellular carcinoma [33], cervical cancer [34], and melanoma [35], caspase-8 was found in high levels within the nucleus. Müller et al had investigated the nuclear expression of caspase-8 in melanoma cells and identified a hitherto unr e p o r t e d n u c l e a r l o c a l i z a t i o n s i g n a l ( N L S ) ( 21 SLKFLSLDY 29 ) and nuclear export signal (NES) ( 468 FTLRKKLVF 476 ), at the N-and C-terminus of caspase-8, respectively, which enable its shuttling between the nucleus and cytosol.…”

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

confidence: 99%

“…Müller et al had investigated the nuclear expression of caspase-8 in melanoma cells and identified a hitherto unr e p o r t e d n u c l e a r l o c a l i z a t i o n s i g n a l ( N L S ) ( 21 SLKFLSLDY 29 ) and nuclear export signal (NES) ( 468 FTLRKKLVF 476 ), at the N-and C-terminus of caspase-8, respectively, which enable its shuttling between the nucleus and cytosol. Only after processing of procaspase-8 into its active form and the removal of the NES-containing N-terminus, caspase-8 remains in the nucleus, proving that the nuclear localization of caspase-8 is possible [35].…”

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%

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

Kostova

Mandal

Becker

et al. 2020

Cancer Metastasis Rev

View full text Add to dashboard Cite

show abstract

“…So far, evidence of the regulation of CYLD expression by pharmacological agents is scarce in the literature, but it has been reported that it may be possible to indirectly regulate CYLD levels by agents acting on CYLD regulatory factors, such as Serum Response Factor (SRF) or kinase inhibitors [1]; also, CYLD levels may be indirectly increased by allosteric inhibition of Caspase 8 (which cleaves CYLD) by the pan-caspase inhibitor zVAD-FMK [47]. Caspase 8 is upregulated and localized to the nucleus in multiple human cancers, correlating with resistance to therapy and poor clinical outcome: it promotes NF-κB-dependent expression of several cytokines, angiogenesis, and tumorigenesis [48], suggesting that the inhibition of Caspase-8 could be an interesting promising regulator of CYLD levels in cancer. In addition, the role of p38 as a mediator of the positive regulation of CYLD expression by SRF has been described [49], suggesting that the use of p38 inhibitors could be an appropriate approximation to favor CYLD-mediated inhibition of skin squamous cell tumor development, since the use of novel, isoform-specific p38 inhibitors has shown that the abrogation of p38δ activity in keratinocytes is accompanied by the simultaneous overactivation of p38α, which in turn can lead to increased CYLD expression through SRF [50][51][52].…”

Section: Relevance Of Wild Type Cyld Expression For Clinical Management Of Skin Sccsmentioning

confidence: 99%

CYLD Inhibits the Development of Skin Squamous Cell Tumors in Immunocompetent Mice

Alameda

García-García

López

et al. 2021

IJMS

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Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.

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“…In the last years, there has been emerging evidence indicating regulatory crosstalk between these cellular networks. It turned out that core components of cell death networks control DNA repair as well as key regulators of the DNA repair machinery play a major role in the cell death (Boege et al, 2017;Alemasova and Lavrik, 2019;Muller et al, 2020). The crosstalk between these networks is rather complex due to several pathways of DNA repair as well as more than a dozen types of programmed cell death that can be initiated upon DNA damage: apoptosis, necroptosis, autophagy, ferroptosis and paranathosis (Galluzzi et al, 2018).…”

Section: Editorial On the Research Topicmentioning

confidence: 99%

Editorial: Dynamical Networks of Life/Death Decisions in a Cell: From DNA Repair to Cell Death

Lavrik

2021

Front. Cell Dev. Biol.

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Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28

Cited by 66 publications

References 49 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

CYLD Inhibits the Development of Skin Squamous Cell Tumors in Immunocompetent Mice

Editorial: Dynamical Networks of Life/Death Decisions in a Cell: From DNA Repair to Cell Death

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