Programming of Cell Resistance to Genotoxic and Oxidative Stress

Velegzhaninov, Ilya O.; Ievlev, Vitaly; Pylina, Yana I.; Shadrin, Dmitry M.; Vakhrusheva, Olesya

doi:10.3390/biomedicines6010005

Cited by 14 publications

(13 citation statements)

References 188 publications

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“…The adaptation to oxidative stress is a highly relevant process and some adaptive pathways focusing on antioxidant defense systems and mitochondrial and metabolic adaptations have been described to be constantly activated in neuronal cells resistant to oxidative stress as well as in AD tissue [6,26,29]. Moreover, oxidative stress resistance has been linked to failure of anticancer therapy and here a particular role of upregulated autophagy and BAG3 has been proposed in various tumor types [16,[67], [68], [69]].…”

Section: Discussionmentioning

confidence: 99%

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

et al. 2019

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Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins. Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator of BAG3-mediated selective macroautophagy and highly relevant for the clearance of aggregated proteins in cells, was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over an important part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.

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Section: Discussionmentioning

confidence: 99%

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

et al. 2019

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“…ROS) that are highly reactive to DNA, and exposure to chemotherapy or radiation therapy. [112][113][114][115][116][117][118] Replication stress can occur even under normal physiological conditions in cancer cells because of a shortage of building blocks (histones, deoxyribonucleotide triphosphates), conflicts between concurrent activation of the massive replication and transcription machineries, as well as unusual DNA structures and topologies. 119,120 As a result of replication fork stalling, levels of exposed single-stranded DNA increase, thereby recruiting RPA (a single-stranded DNAbinding protein) to the lesion.…”

Section: Genotoxic Stressmentioning

confidence: 99%

“…The threats can arise from a broad range of events and agents, including unresolved replication fork stalling during normal DNA replication, accumulation of metabolic intermediates (e.g. ROS) that are highly reactive to DNA, and exposure to chemotherapy or radiation therapy . Replication stress can occur even under normal physiological conditions in cancer cells because of a shortage of building blocks (histones, deoxyribonucleotide triphosphates), conflicts between concurrent activation of the massive replication and transcription machineries, as well as unusual DNA structures and topologies .…”

Section: Genotoxic Stressmentioning

confidence: 99%

Therapeutic targeting of cellular stress responses in cancer

Chen

Xie

2018

Thoracic Cancer

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Similar to bacteria, yeast, and other organisms that have evolved pathways to respond to environmental stresses, cancer cells develop mechanisms that increase genetic diversity to facilitate adaptation to a variety of stressful conditions, including hypoxia, nutrient deprivation, exposure to DNA‐damaging agents, and immune responses. To survive, cancer cells trigger mechanisms that drive genomic instability and mutation, alter gene expression programs, and reprogram the metabolic pathways to evade growth inhibition signaling and immune surveillance. A deeper understanding of the molecular mechanisms that underlie the pathways used by cancer cells to overcome stresses will allow us to develop more efficacious strategies for cancer therapy. Herein, we overview several key stresses imposed on cancer cells, including oxidative, metabolic, mechanical, and genotoxic, and discuss the mechanisms that drive cancer cell responses. The therapeutic implications of these responses are also considered, as these factors pave the way for the targeting of stress adaption pathways in order to slow cancer progression and block resistance to therapy.

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“…The adaptation to oxidative stress is a highly relevant process and some adaptive pathways focusing on antioxidant defense systems and mitochondrial and metabolic adaptations have been described to be constantly activated in neuronal cells resistant to oxidative stress as well as in AD tissue [26], [29], [6]. Moreover, oxidative stress resistance has been linked to failure of anticancer therapy and here a particular role of upregulated autophagy and BAG3 has been proposed in various tumor types [16], [65], [66], [67].…”

Section: Discussionmentioning

confidence: 99%

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Chakraborty

Felzen

Hiebel

et al. 2019

Preprint

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Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins.Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator of BAG3-mediated selective macroautophagy and highly relevant for the clearance of aggregated proteins in cells was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over a key part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.

show abstract

Programming of Cell Resistance to Genotoxic and Oxidative Stress

Cited by 14 publications

References 188 publications

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Therapeutic targeting of cellular stress responses in cancer

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

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