Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes

Nitobe, Joji; Yamaguchi, Seiji; Okuyama, Masaki; Nakatani, Naoki; Sata, Masataka; Miyamoto, Takuya; Takeishi, Yasuchika; Kubota, Isao; Tomoike, Hitonobu

doi:10.1016/s0008-6363(02)00646-6

Cited by 120 publications

(89 citation statements)

References 44 publications

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“…ROS mediate Wit A-induced c-FLIP down-regulation by inhibiting NF-κB signaling pathways ROS down-regulate c-FLIP levels and increase the sensitivity to apoptotic stimuli [23,24]. As shown in Fig.…”

Section: Down-regulation Of C-flip Also Contributes To Wit A-stimulatmentioning

confidence: 89%

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

Lee

Min

et al. 2009

Free Radical Biology and Medicine

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Section: Down-regulation Of C-flip Also Contributes To Wit A-stimulatmentioning

confidence: 89%

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

Lee

Min

et al. 2009

Free Radical Biology and Medicine

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“…Almost a decade ago, studies of cardiac myocytes showed a requirement for ROS generation by doxorubicin to trigger a loss of c-FLIP protein and subsequent sensitization of cells to Fas-induced apoptosis (48). A later study demonstrated that Fas ligand generated ROS in normal lung epithelial cells through activation of Rac1 and the NADPH oxidase.…”

Section: Discussionmentioning

confidence: 99%

Novel Phosphorylation and Ubiquitination Sites Regulate Reactive Oxygen Species-dependent Degradation of Anti-apoptotic c-FLIP Protein

Wilkie-Grantham

Matsuzawa

Reed

2013

Journal of Biological Chemistry

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Background:The anti-apoptotic protein c-FLIP inhibits cell death induced by TNF family cytokines, including TRAIL. Results: Reactive oxygen species (ROS)-dependent phosphorylation and ubiquitination of the c-FLIP protein causes its proteasome-mediated degradation, thus sensitizing to TRAIL-induced cell death. Conclusion: ROS-dependent post-translational modifications regulate c-FLIP protein stability. Significance: Understanding how ROS mediate c-FLIP protein degradation may inform therapeutic strategies targeting cell death mechanisms.

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“…Specifically, rat-derived embryonic cardiomyocytes, which are normally resistant to FAS-L induced apoptosis [41], may get sensitized to FAS-L when pre-exposed to DOX [49,50]. Interestingly, DOX pre-exposure may also induce increased FAS-L released by rat-derived embryonic cardiomyocytes [41], suggesting a DOX-sensitization dependent autocrine/paracrine mechanism for cardiac apoptosis induction.…”

Section: Does Dox Exposure Change Apoptosis Likelihood To Later Somatmentioning

confidence: 99%

“…This work has been supported by the Bijzonder Onderzoeksfonds of the KU Leuven (PF/10/014) to H. J. H. shown to release FAS-L after DOX [41] while getting also sensitized to DOX and respond to it in an auto/paracrine manner [49]. (E) Due to the absence of cytochrome-c in the mitochondrial inter membrane space, MOMP can lead to a bioenergetics crisis with loss of mitochondrial polarization, reduced ATP production, failure of ionic homeostasis.…”

Section: Acknowledgementmentioning

confidence: 99%

“…(Left panel) Cardiomyocytes exposed to DOX have a tendency to change from oxidative to glycolytic mechanism and to show a functional impairment [5,63], potentially also associated with a switch to fetal gene expression program [87] {Hrelia, 2002 #97}. Likewise, while cardiomyocytes have acquired apoptosis resistance during differentiation [46], DOX exposure may change the balance of pro-and anti-apoptotic proteins in favor of the latter [25,88] or sensitize cardiomyocytes to cell death ligands [49].…”

Section: Acknowledgementmentioning

confidence: 99%

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Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes

Abstract: FLIP, an inhibitor of apoptosis induced by cytokines of TNF family, contributes at least partly to Dox-induced sensitization to Fas-mediated apoptosis in cardiac myocytes. The expression of FLIP in cardiac myocytes is regulated by ROS.

Cited by 120 publications

References 44 publications

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

Novel Phosphorylation and Ubiquitination Sites Regulate Reactive Oxygen Species-dependent Degradation of Anti-apoptotic c-FLIP Protein

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

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