Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

Deegan, Shane; Saveljeva, Svetlana; Gorman, Adrienne M.; Samali, Afshin

doi:10.1007/s00018-012-1173-4

Cited by 242 publications

(176 citation statements)

References 153 publications

(197 reference statements)

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“…However, when ER stress is prolonged or too severe, these mechanisms fail to restore proteostasis leading to cell death. [77][78][79] This may explain that mild injury did not affect neuronal survival, as well as total number of activated microglia in the brain. ER stress significantly increases in an injury …”

Section: Disrupted Brain Neurogenesis/er Stress Aftermentioning

confidence: 97%

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Zhao

Kumar

et al. 2016

Journal of Neurotrauma

107

100

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Clinical and experimental studies show that spinal cord injury (SCI) can cause cognitive impairment and depression that can significantly impact outcomes. Thus, identifying mechanisms responsible for these less well-examined, important SCI consequences may provide targets for more effective therapeutic intervention. To determine whether cognitive and depressive-like changes correlate with injury severity, we exposed mice to sham, mild, moderate, or severe SCI using the Infinite Horizon Spinal Cord Impactor and evaluated performance on a variety of neurobehavioral tests that are less dependent on locomotion. Cognitive impairment in Y-maze, novel objective recognition, and step-down fear conditioning tasks were increased in moderate-and severe-injury mice that also displayed depressive-like behavior as quantified in the sucrose preference, tail suspension, and forced swim tests. Bromo-deoxyuridine incorporation with immunohistochemistry revealed that SCI led to a long-term reduction in the number of newly-generated immature neurons in the hippocampal dentate gyrus, accompanied by evidence of greater neuronal endoplasmic reticulum (ER) stress. Stereological analysis demonstrated that moderate/severe SCI reduced neuronal survival and increased the number of activated microglia chronically in the cerebral cortex and hippocampus. The potent microglial activator cysteine-cysteine chemokine ligand 21 (CCL21) was elevated in the brain sites after SCI in association with increased microglial activation. These findings indicate that SCI causes chronic neuroinflammation that contributes to neuronal loss, impaired hippocampal neurogenesis and increased neuronal ER stress in important brain regions associated with cognitive decline and physiological depression. Accumulation of CCL21 in brain may subserve a pathophysiological role in cognitive changes and depression after SCI.

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Section: Disrupted Brain Neurogenesis/er Stress Aftermentioning

confidence: 97%

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Zhao

Kumar

et al. 2016

Journal of Neurotrauma

107

100

View full text Add to dashboard Cite

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“…Autophagy can be activated during a time of cell stress and serves as an escape mechanism for cells exposed to cytotoxic agents, hypoxia, or a reduced nutrient environment (32). To test whether NEO212 regulates autophagy, glioma cells were treated with this drug or temozolomide (Fig.…”

Section: Neo212 Induces Glioma Cell Cytotoxicity Through Several Pathmentioning

confidence: 99%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O 6 methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O 6 -benzylguanine (O 6 BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomideresistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.

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“…The ER is a complex organelle that has numerous cellular functions. The up-regulation of autophagy is an essential prosurvival response to the ER stress caused by unfolded/misfolded proteins and the aggregation of proteins, which results in protein or organelle damage (21)(22)(23). The molecular events that occur during autophagy induction include the association of autophagy-related protein 8 (ATG8)/LC3 with autophagosomal membranes through its conjugation to the lipid phosphatidylethanolamine and the formation of autophagosomes (24,25).…”

mentioning

confidence: 99%

The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway

Jia¹,

Lin²,

Chen

et al. 2016

Journal of Biological Chemistry

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Autophagy is an evolutionarily conserved degradative process that allows cells to maintain homoeostasis in numerous physiological situations. This process also functions as an essential protective response to endoplasmic reticulum (ER) stress, which promotes the removal and degradation of unfolded proteins. However, little is known regarding the mechanism by which autophagy is initiated and regulated in response to ER stress. In this study, different types of autophagy were identified in human gastric cancer MKN45 cells in response to the stress induced by nutrient starvation or lipotoxicity in which the regulation of these pathways is mammalian target of rapamycin (mTOR)-dependent or -independent, respectively. Interestingly, we found that p8, a stress-inducible transcription factor, was enhanced in MKN45 cells treated with palmitic acid to induce lipotoxicity. Furthermore, an increase in autophagy was observed in MKN45 cells stably overexpressing p8 using a lentivirus system, and autophagy induced by palmitic acid was blocked by p8 RNAi compared with the control. Western blotting analyses showed that autophagy was regulated by p8 or mTOR in response to the protein kinase-like endoplasmic reticulum kinase/activating transcription factor 6-mediated ER stress of lipotoxicity or the parkin-mediated mitochondrial stress of nutrient starvation, respectively. Furthermore, our results indicated that autophagy induced by palmitic acid is mTOR-independent, but this autophagy pathway was regulated by p8 via p53-and PKC␣-mediated signaling in MKN45 cells. Our findings provide insights into the role of p8 in regulating autophagy induced by the lipotoxic effects of excess fat accumulation in cells.Autophagy is a phenomenon in which cytoplasmic components are delivered to the lysosomes for bulk degradation in response to prolonged starvation periods, nutritional fluctuations in the environment, developmental tissue remodeling, organelle quality control, or immune responses (1-3). Recent studies have shown that the dysregulation of autophagy is implicated in the physiopathology of major diseases such as cancer, neurodegenerative disorders, and diabetes (4 -8). The autophagy process involves more than 30 autophagy-related genes and can be divided into several physiologically continuous steps (including induction, cargo recognition and packaging, and vesicle formation and breakdown) (9 -11). As a key energy sensor, AMP-activated protein kinase (AMPK) 3 regulates the cellular metabolism to maintain energy homoeostasis and promotes autophagy by activating UNC-51-like kinase 1 (ULK1) through the phosphorylation of its Ser-317 and Ser-777 residues. Conversely, the central cell growth regulator mammalian target of rapamycin (mTOR) inhibits autophagy by phosphorylating Ser-757 of ULK1 and disrupting its interaction with AMPK (12-16). This coordinated pattern of phosphorylation is important for the proper control of autophagy.Autophagy can be nonselective or selective. Non-selective bulk degradation of the cytoplasm and organelles by ...

show abstract

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress

Cited by 242 publications

References 153 publications

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway

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