Compensatory activation of ERK1/2 in<i>Atg5</i>-deficient mouse embryo fibroblasts suppresses oxidative stress-induced cell death

Pyo, Jong-Ok; Nah, Jihoon; Kim, Hyojin; Lee, Ho‐June; Heo, Jungun; Lee, Heuiran; Jung, Yong‐Keun

doi:10.4161/auto.5525

Cited by 35 publications

(57 citation statements)

References 33 publications

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“…7,9,[12][13][14][15][16]21 However, in these studies, the intracellular levels of O 15 This could be due to cell-type-specific differences or the lack of determination of the relative amounts of O 2 KÀ and H 2 O 2 produced by AA starvation. Nevertheless, ROS could act further downstream by oxidizing Atg-4 and/or increasing beclin-1 expression leading to induction of autophagy.…”

Section: Superoxide (Omentioning

confidence: 62%

“…Several reports have suggested that starvation-induced autophagy is mediated by ROS. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] In this study, we investigated the generation of O 2 KÀ and H 2 O 2 under two starvation conditions: starvation of glucose, L-glutamine, pyruvate, and serum (GP), and starvation of amino acids and serum (AA). Cellular levels of O 2 KÀ and H 2 O 2 were measured by flow cytometry using specific fluorescent dyes (see Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

“…When another autophagy inhibitor wortmannin (Supplementary Figure S4bi) was used in HeLa cells, the levels of both O 2 KÀ and H 2 O 2 induced by GP or AA starvation were not significantly affected (Figure 8b). In addition, beclin-1 and atg-7 siRNAs knockdown failed to significantly affect GP or AA starvation- demonstrated in many studies, [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] KÀ are also reduced through a chain reaction. 2,3 This illustrates the importance for measuring all forms of ROS.…”

Section: Superoxide (Omentioning

confidence: 99%

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Superoxide is the major reactive oxygen species regulating autophagy

2009

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Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O 2 KÀ ) and hydrogen peroxide (H 2 O 2 ). However, the relative functions of O 2 KÀ and H 2 O 2 in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H 2 O 2 . We found that O 2 KÀ was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O 2 KÀ and H 2 O 2 . Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O 2 KÀ levels but increased H 2 O 2 levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O 2 KÀ and H 2 O 2 levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O 2 KÀ levels, lowered H 2 O 2 levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H 2 O 2 induced autophagy and increased intracellular O 2 KÀ but failed to increase intracellular H 2 O 2 . Taken together, these findings indicate that O 2 KÀ is the major ROS-regulating autophagy.

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Section: Superoxide (Omentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Superoxide (Omentioning

confidence: 99%

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Superoxide is the major reactive oxygen species regulating autophagy

2009

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“…3C and 3D) and medium ( In previous studies 33,48 atg5 -/-MEFs were found to be protected from oxidative stress and to display a decreased accumulation of carbonylated/oxidized proteins as compared to their wild-type counterparts (Atg5 +/+ MEFs), 33 due to the upregulation of compensatory mechanisms (like chaperone-mediated autophagy) 33,48 in these untreated MEFs. 33,49 Indeed, early after Hyp-PDT (1 h) we observed that, while Atg5 +/+ MEFs exhibited the characteristic increase in carbonylated proteins yet atg5 -/-MEFs displayed a reduced accumulation of ROS-damaged (i.e. carbonylated) proteins (Fig.…”

Section: Ecto-calr Induced By Hyp-pdt Correlates With the Accumulatiomentioning

confidence: 97%

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

et al. 2013

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Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy-induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy-induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT-treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants

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“…Nevertheless, the same autophagy-deficient MEFs were more sensitive to cell death triggered by TNFa. 5 Interestingly, inhibiting autophagy was found to prevent apoptosis in sarcoma cells following TNFa treatment in combination with NFkB suppression, 6 or apoptosis in nontransformed fibroblasts followed by ER stress. 7 Reactive oxygen species (ROS) play an important role in different types of cell death.…”

Section: Introductionmentioning

confidence: 99%

Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation

et al. 2012

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Autophagy is a catabolic process involved in the turnover of organelles and macromolecules which, depending on conditions, may lead to cell death or preserve cell survival. We found that some lung cancer cell lines and tumor samples are characterized by increased levels of lipidated LC3. Inhibition of autophagy sensitized non-small cell lung carcinoma (NSCLC) cells to cisplatin-induced apoptosis; however, such response was attenuated in cells treated with etoposide. Inhibition of autophagy stimulated ROS formation and treatment with cisplatin had a synergistic effect on ROS accumulation. Using genetically encoded hydrogen peroxide probes directed to intracellular compartments we found that autophagy inhibition facilitated formation of hydrogen peroxide in the cytosol and mitochondria of cisplatin-treated cells. The enhancement of cell death under conditions of inhibited autophagy was partially dependent on caspases, however, antioxidant NAC or hydroxyl radical scavengers, but not the scavengers of superoxide or a MnSOD mimetic, reduced the release of cytochrome c and abolished the sensitization of the cells to cisplatin-induced apoptosis. Such inhibition of ROS prevented the processing and release of AIF (apoptosis-inducing factor) and HTRA2 from mitochondria. Furthermore, suppression of autophagy in NSCLC cells with active basal autophagy reduced their proliferation without significant effect on the cell-cycle distribution. Inhibition of cell proliferation delayed accumulation of cells in the S phase upon treatment with etoposide that could attenuate the execution stage of etoposide-induced apoptosis. These findings suggest that autophagy suppression leads to inhibition of NSCLC cell proliferation and sensitizes them to cisplatininduced caspase-dependent and -independent apoptosis by stimulation of ROS formation.

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Compensatory activation of ERK1/2 inAtg5-deficient mouse embryo fibroblasts suppresses oxidative stress-induced cell death

Cited by 35 publications

References 33 publications

Superoxide is the major reactive oxygen species regulating autophagy

Superoxide is the major reactive oxygen species regulating autophagy

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation

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