A fate worse than death: apoptosis as an oncogenic process

Ichim, Gabriel; Tait, Stephen W.G.

doi:10.1038/nrc.2016.58

Cited by 366 publications

(335 citation statements)

References 156 publications

(130 reference statements)

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“…Yet, DOX susceptibility to apoptosis in other relevant cells such as in bovine aortic endothelial cells were also reported and apoptosis may act in a p53-dependent and independent way [81]. Consistent with our focus on cardiomyocytes, we have further limited the discussion of sub lethal caspase-activation to structural remodeling and not considered other potential effects such as caspase-induced cellular hyper-proliferation, potentially relevant in other cardiac cells [82].…”

Section: Limitations Of Current Studies On the Effect Of Dox Exposuresupporting

confidence: 58%

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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Section: Limitations Of Current Studies On the Effect Of Dox Exposuresupporting

confidence: 58%

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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“…Apoptosis is a programmed cell death with controllable intracellular mechanisms, pathologically featuring maintenance of ATP levels and condensed nuclei inside shrunken cells as the consequences of activated caspase cascades (Ichim & Tait, 2016; Nagata & Tanaka, 2017), whereas necrosis has been regarded as an acute type of cell death, which is characterized by ATP deprivation, swollen cytoplasm, and cell lysis. In contrast to apoptosis, necrosis is a rapid cellular reaction without programmed procedures, which makes it more difficult to control or reverse by therapeutic intervention (Gorman, 2008; Nikolova, Roos, Krämer, Strik, & Kaina, 2017).…”

Section: Necrosis: Autophagy‐related Cell Death That Contributes To Tmentioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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“…The apoptotic process is comprised of two main pathways, the death receptor pathway (extrinsic) and the mitochondrial mediated pathway (intrinsic) (Czabotar et al 2014;Elmore 2007;Ichim and Tait 2016;Tait and Green 2010) and are summarized schematically in Fig. 1.…”

Section: Introduction: Initiation Of Mompmentioning

confidence: 99%

“…These pathways converge at an execution pathway involving activation of caspase 3/7 by caspase 8/9 for the initiation of the cell death. As a result, the cell forms into small apoptotic bodies which are then engulfed by phagocytosis (Elmore 2007;Fulda and Debatin 2006;Ichim and Tait 2016). These pathways are not completely independent of each other, and often activation via one pathway will induce the other (Chen et al 2015;Kaufmann and Hengartner 2001;Wong 2011).…”

Section: Introduction: Initiation Of Mompmentioning

confidence: 99%

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

et al. 2017

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Apoptosis is important in regulating cell death turnover and is mediated by the intrinsic and death receptor-based extrinsic pathways which converge at the mitochondrial outer membrane (MOM) leading to mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of apoptotic proteins that further activate the downstream pathway of apoptosis. Thus, tight regulation of MOMP is crucial in controlling apoptosis, and a lack of control may lead to tissue and organ malformation and the development of cancers. Despite a growing number of studies focusing on the structure and activity of the proteins involved in mediating MOMP, such as the Bcl-2 family proteins, the mechanism of MOMP is not well understood. In particular, the crucial role of the various structural properties and changes in lipid components of the MOM in mediating the recruitment and activation of different Bcl-2 proteins remains poorly understood. Furthermore, the factors that control the changes in mitochondrial membrane integrity from the initiation to the final disruption of MOM have yet to be clearly defined. In this review, we provide an overview of studies that focus on the mitochondrial membrane with a biophysical analysis of the interactions of the Bcl-2 proteins with the mitochondrial membrane.

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A fate worse than death: apoptosis as an oncogenic process

Cited by 366 publications

References 156 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

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