Yessotoxin induces ER-stress followed by autophagic cell death in glioma cells mediated by mTOR and BNIP3

Rubiolo, Juan A.; López-Alonso, Henar; Martı́nez, Paulino; Millán, Adrián; Cagide, Eva; Vieytes, Mercedes R.; Vega, Félix; Botana, Luís M.

doi:10.1016/j.cellsig.2013.10.004

Cited by 78 publications

(58 citation statements)

References 62 publications

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“…Therefore, autophagy could be activated as cellular nutrients necessity (Klionsky and Emr, 2000;Ohyashiki et al, 2009). It has been described that YTX activates different types of programmed cell death, and recently, the autophagy activation after the treatment with this toxin was pointed in human glioma cells (Korsnes, 2012;Rubiolo et al, 2014). Furthermore, previous works have shown that in the first 24 h of YTX exposure, caspase 8 was activated in K-562 cells, but after 48 h this activation disappears (Fernández-Araujo et al, 2014).…”

Section: Discussionmentioning

confidence: 96%

Key role of phosphodiesterase 4A (PDE4A) in autophagy triggered by yessotoxin

Fernández-Araujo¹,

Alfonso²,

Vieytes³

et al. 2015

Toxicology

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Understanding the mechanism of action of the yessotoxin (YTX) is crucial since this drug has potential pharmacological effects in allergic processes, tumor proliferation and neurodegenerative diseases. It has been described that YTX activates apoptosis after 24h of treatment, while after 48 h of incubation with the toxin a decrease in cell viability corresponding to cellular differentiation or non-apoptotic cell death was observed. In this paper, these processes were extensively studied by using the erythroleukemia K-562 cell line. On one hand, events of K-562 cell differentiation into erythrocytes after YTX treatment were studied using hemin as positive control of cell differentiation. Cell differentiation was studied through the cyclic nucleotide response element binding (phospho-CREB) and the transferrin receptor (TfR) expression. On the other hand, using rapamycin as positive control, autophagic hallmarks, as non-apoptotic cell death, were studied after toxin exposure. In this case, the mechanistic target of rapamycin (mTOR) and light chain 3B (LC3B) levels were measured to check autophagy activation. The results showed that cell differentiation was not occurring after 48 h of toxin incubation while at this time the autophagy was triggered. Furthermore after 24h of toxin treatment none of these processes were activated. In addition, the role of the type 4A phosphodiesterase (PDE4A), the intracellular target of YTX, was checked. PDE4A-silencing experiments showed different regulation steps of PDE4A in the autophagic processes triggered either by traditional compounds or YTX. In summary, after 48 h YTX treatment PDE4A-dependent autophagy, as non-apoptotic programmed cell death, is activated.

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Section: Discussionmentioning

confidence: 96%

Key role of phosphodiesterase 4A (PDE4A) in autophagy triggered by yessotoxin

Fernández-Araujo¹,

Alfonso²,

Vieytes³

et al. 2015

Toxicology

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“…Activation of ER stress can also affect autophagic flux, which may lead to cell death (Tripathi et al, 2016). Trib3, as a novel ER stress-inducible gene, is involved in autophagic cell death by inducing ER-stress, activating UPR reaction and through mTOR signaling pathway (Ohoka et al, 2005; Rubiolo et al, 2014). Studies have shown that upregulation of the expression of Trib3 can promote the inhibitory interaction of AKT with its upsteam kinases and lead to inhibition of AKT/mTORC1 axis and autophagy-mediated cell death (Salazar et al, 2015; Erazo et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Huang

Tai

et al. 2017

Front. Mol. Neurosci.

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Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH exposure causes detrimental effects on multiple organ systems, primarily the nervous system, especially dopaminergic pathways, in both laboratory animals and humans. In this study, we hypothesized that Nuclear protein 1 (Nupr1/com1/p8) is involved in METH-induced neuronal apoptosis and autophagy through endoplasmic reticulum (ER) stress signaling pathway. To test this hypothesis, we measured the expression levels of Nupr1, ER stress protein markers CHOP and Trib3, apoptosis-related protein markers cleaved-caspase3 and PARP, as well as autophagy-related protein markers LC3 and Beclin-1 in brain tissues of adult male Sprague-Dawley (SD) rats, rat primary cultured neurons and the rat adrenal pheochromocytoma cells (PC12 cells) after METH exposure. We also determined the effects of METH exposure on the expression of these proteins after silencing Nupr1, CHOP, or Trib3 expression with synthetic small hairpin RNA (shRNA) or siRNA in vitro, and after silencing Nupr1 in the striatum of rats by injecting lentivirus containing shRNA sequence targeting Nupr1 gene to rat striatum. The results showed that METH exposure increased Nupr1 expression that was accompanied with increased expression of ER stress protein markers CHOP and Trib3, and also led to apoptosis and autophagy in rat primary neurons and in PC12 cells after 24 h exposure (3.0 mM), and in the prefrontal cortex and striatum of rats after repeated intraperitoneal injections (15 mg/kg × 8 injections at 12 h intervals). Silencing of Nupr1 expression partly reduced METH-induced apoptosis and autophagy in vitro and in vivo. These results suggest that Nupr1 plays an essential role in METH-caused neuronal apoptosis and autophagy at relatively higher doses and may be a potential therapeutic target in high-dose METH-induced neurotoxicity.

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“…Autophagy is a cellular degradation process initiated in response to stress, which attempts to restore metabolic homeostasis through the catabolic lysis of aggregated proteins, unfolded/misfolded proteins, or damaged subcellular organelles (Mizushima, ). Although most studies indicate that autophagy has a pro‐survival function following ER stress (Cheng, Chang, Chen, & Chen, ; Ma et al, ), a heightened degree/duration of stress can induce autophagy‐dependent cell death mechanisms, and lead to cell damage (Rubiolo et al, ).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress

Song

Tan

Miao

et al. 2017

Journal Cellular Physiology

423

283

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Endoplasmic reticulum (ER) stress is a common cellular stress response that is triggered by a variety of conditions that disturb cellular homeostasis, and induces cell apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis induced by ER stress. There are common upstream signaling pathways between autophagy and apoptosis induced by ER stress, including PERK/ATF4, IRE1α, ATF6, and Ca . Autophagy can not only block the induction of apoptosis by inhibiting the activation of apoptosis-associated caspase which could reduce cellular injury, but also help to induce apoptosis. In addition, the activation of apoptosis-related proteins can also inhibit autophagy by degrading autophagy-related proteins, such as Beclin-1, Atg4D, Atg3, and Atg5. Although the interactions of different autophagy- and apoptosis-related proteins, and also common upstream signaling pathways have been found, the potential regulatory mechanisms have not been clearly understood. In this review, we summarize the dual role of autophagy, and the interplay and potential regulatory mechanisms between autophagy and apoptosis under ER stress condition.

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Yessotoxin induces ER-stress followed by autophagic cell death in glioma cells mediated by mTOR and BNIP3

Cited by 78 publications

References 62 publications

Key role of phosphodiesterase 4A (PDE4A) in autophagy triggered by yessotoxin

Key role of phosphodiesterase 4A (PDE4A) in autophagy triggered by yessotoxin

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress

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