“…As PKC has recently been implicated in ferroptosis in a model of Parkinson's disease, we investigated the involvement of PKC in the control of ferroptosis in RMS cells. To screen for a potential involvement of PKC, we used the broad‐range PKC inhibitor Bim1 that targets different isoforms .…”
Section: Resultsmentioning
confidence: 99%
“…In addition, genetic silencing of PKCα protected RMS cells from Erastin‐induced cell death emphasizing the involvement of PKCα in ferroptotic signaling. Interestingly, PKCα has recently been described to initiate ferroptotic cell death in dopaminergic neurons in a model of Parkinson's disease . In addition, PKC isoforms have been described as upstream activators of NOX through phosphorylation .…”
Recent data suggest that rhabdomyosarcoma (RMS) cells might be vulnerable to oxidative stress‐induced cell death. Here, we show that RMS are susceptible to cell death induced by Erastin, an inhibitor of the glutamate/cystine antiporter xc− that can increase reactive oxygen species (ROS) production via glutathione (GSH) depletion. Prior to cell death, Erastin caused GSH depletion, ROS production and lipid peroxidation. Importantly, pharmacological inhibitors of lipid peroxidation (i.e., Ferrostatin‐1, Liproxstatin‐1), ROS scavengers (i.e., α‐Tocopherol, GSH) and the iron chelator Deferoxamine inhibited ROS accumulation, lipid peroxidation and cell death, consistent with ferroptosis. Interestingly, the broad‐spectrum protein kinase C (PKC) inhibitor Bisindolylmaleimide I as well as the PKCα‐ and β‐selective inhibitor Gö6976 significantly reduced Erastin‐induced cell death. Similarly, genetic knockdown of PKCα significantly protected RMS cells from Erastin‐induced cell death. Furthermore, the broad‐spectrum nicotinamide adenine dinucleotide phosphate‐oxidase (NOX) inhibitor Diphenyleneiodonium and the selective NOX1/4 isoform inhibitor GKT137831 significantly decreased Erastin‐stimulated ROS, lipid ROS and cell death. These data provide new insights into the molecular mechanisms of ferroptosis in RMS, contributing to the development of new redox‐based treatment strategies.
“…As PKC has recently been implicated in ferroptosis in a model of Parkinson's disease, we investigated the involvement of PKC in the control of ferroptosis in RMS cells. To screen for a potential involvement of PKC, we used the broad‐range PKC inhibitor Bim1 that targets different isoforms .…”
Section: Resultsmentioning
confidence: 99%
“…In addition, genetic silencing of PKCα protected RMS cells from Erastin‐induced cell death emphasizing the involvement of PKCα in ferroptotic signaling. Interestingly, PKCα has recently been described to initiate ferroptotic cell death in dopaminergic neurons in a model of Parkinson's disease . In addition, PKC isoforms have been described as upstream activators of NOX through phosphorylation .…”
Recent data suggest that rhabdomyosarcoma (RMS) cells might be vulnerable to oxidative stress‐induced cell death. Here, we show that RMS are susceptible to cell death induced by Erastin, an inhibitor of the glutamate/cystine antiporter xc− that can increase reactive oxygen species (ROS) production via glutathione (GSH) depletion. Prior to cell death, Erastin caused GSH depletion, ROS production and lipid peroxidation. Importantly, pharmacological inhibitors of lipid peroxidation (i.e., Ferrostatin‐1, Liproxstatin‐1), ROS scavengers (i.e., α‐Tocopherol, GSH) and the iron chelator Deferoxamine inhibited ROS accumulation, lipid peroxidation and cell death, consistent with ferroptosis. Interestingly, the broad‐spectrum protein kinase C (PKC) inhibitor Bisindolylmaleimide I as well as the PKCα‐ and β‐selective inhibitor Gö6976 significantly reduced Erastin‐induced cell death. Similarly, genetic knockdown of PKCα significantly protected RMS cells from Erastin‐induced cell death. Furthermore, the broad‐spectrum nicotinamide adenine dinucleotide phosphate‐oxidase (NOX) inhibitor Diphenyleneiodonium and the selective NOX1/4 isoform inhibitor GKT137831 significantly decreased Erastin‐stimulated ROS, lipid ROS and cell death. These data provide new insights into the molecular mechanisms of ferroptosis in RMS, contributing to the development of new redox‐based treatment strategies.
“…These inhibitors are also protective in models of degenerative brain disorders, including Parkinson's, Huntington's, and Alzheimer's Diseases, as well as in other forms of neurodegeneration and traumatic and hemorrhagic brain injury (Chen et al, 2015; Do Van et al, 2016; Gascon et al, 2016; Guiney et al, 2017; Hambright et al, 2017; Li et al, 2017; Skouta et al, 2014; Zille et al, 2017). Ferroptosis in some other tissues and diseases has been examined, including liver hemochromatosis (Wang et al, 2017).…”
Section: Links Between Ferroptosis and Pathologymentioning
Summary
Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and that cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
“…The presence of soluble oligomeric species of oxidised α-syn within close proximity to synaptic vesicle membrane may also lead to ROS-induced lipid peroxidation and subsequent release of DA incorporated through the already impaired VMAT2 mechanism. An iron and lipid dependent form of cell death called ferroptosis has recently been identified as a major feature in models of PD [142]. The oxidation of α-syn may be a key component of this pathway that requires further investigation.Fig.…”
Section: Posttranslational Modifications To α-Synuclein Increase Vulnmentioning
Parkinson’s disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson’s disease.
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