ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Dewaele, Michael; Maes, Hannelore; Agostinis, Patrizia

doi:10.4161/auto.6.7.12113

Cited by 276 publications

(212 citation statements)

References 153 publications

(218 reference statements)

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“…In line with a tumor-protecting role for autophagy, tumor cells induce autophagy in response to most anticancer therapies and utilize autophagy to overcome the therapeutically induced stress and cellular damage [176,177,183]. In these cases, autophagy inhibition might enhance the efficacy of anticancer treatments.…”

Section: Autophagy In Tumorigenesis and Cancer Treatmentmentioning

confidence: 99%

Autophagy: for better or for worse

et al. 2011

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Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.

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Section: Autophagy In Tumorigenesis and Cancer Treatmentmentioning

confidence: 99%

Autophagy: for better or for worse

et al. 2011

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“…18 It is also worth noting that oxidative stress has been proposed to induce autophagy by specifically regulating autophagy protein ATG4; 19 however, recent studies also show that the type of oxidant generated and its site of origin are crucial factors in determining whether it would lead to autophagic stimulation. 20 Rapamycin is an immunosuppressant antibiotic widely used as an inducer of autophagy, acting through its inhibitory effect on the mechanistic target of rapamycin (MTOR). 21 In the presence of nutrients and growth factors, MTOR is active, hyperphosphorylating and inhibiting the unc-51-like kinase 1-ATG13-RB1 inducible coiled-coil protein (ULK1-ATG13-RB1CC1) complex required for the induction of autophagy.…”

Section: Ama Increases Mitochondrial Omentioning

confidence: 99%

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

et al. 2013

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“…7,8 Activation of autophagy in response to the increased status of oxidative stress during cancer progression and in response to anticancer therapy plays a role in the modulation of cellular redox homeostasis with consequences that depend on the genetic background of the cancer cells, their ability to undergo apoptosis, progression stage and type of ROS insults. [9][10][11] At the molecular level, both hydrogen peroxide (H 2 O 2 ) and superoxide radical (O 2 •-) have been proposed as signaling mediators in autophagy. 11 Scherz-Shouval et al 12 showed that H 2 O 2 PD stress.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] At the molecular level, both hydrogen peroxide (H 2 O 2 ) and superoxide radical (O 2 •-) have been proposed as signaling mediators in autophagy. 11 Scherz-Shouval et al 12 showed that H 2 O 2 PD stress. 31 The alleviation of both autophagic and apoptotic processes by overexpression of the cytosolic membrane-associated antioxidant enzyme GPX4 (phospholipid glutathione peroxidase) already revealed a role for ROS originated at the ER in the further propagation of oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal autophagic degradation of oxidatively damaged organelles after photodynamic stress is amplified by mitochondrial reactive oxygen species

et al. 2012

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Although reactive oxygen species (ROS) have been reported to evoke different autophagic pathways, how ROS or their secondary products modulate the selective clearance of oxidatively damaged organelles is less explored. To investigate the signaling role of ROS and the impact of their compartmentalization in autophagy pathways, we used murine fibrosarcoma L929 cells overexpressing different antioxidant enzymes targeted to the cytosol or mitochondria and subjected them to photodynamic (PD) stress with the endoplasmic reticulum (ER)-associated photosensitizer hypericin. We show that following apical ROS-mediated damage to the ER, predominantly cells overexpressing mitochondria-associated glutathione peroxidase 4 (GPX4) and manganese superoxide dismutase (SOD2) displayed attenuated kinetics of autophagosome formation and overall cell death, as detected by computerized time-lapse microscopy. Consistent with a primary ER photodamage, kinetics and colocalization studies revealed that photogenerated ROS induced an initial reticulophagy, followed by morphological changes in the mitochondrial network that preceded clearance of mitochondria by mitophagy. Overexpression of cytosolic and mitochondria-associated GPX4 retained the tubular mitochondrial network in response to PD stress and concomitantly blocked the progression toward mitophagy. Preventing the formation of phospholipid hydroperoxides and H2O2 in the cytosol as well as in the mitochondria significantly reduced cardiolipin peroxidation and apoptosis. All together, these results show that in response to apical ER photodamage ROS propagate to mitochondria, which in turn amplify ROS production, thereby contributing to two antagonizing processes, mitophagy and apoptosis

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ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Cited by 276 publications

References 153 publications

Autophagy: for better or for worse

Autophagy: for better or for worse

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

Spatiotemporal autophagic degradation of oxidatively damaged organelles after photodynamic stress is amplified by mitochondrial reactive oxygen species

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