Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway

Byun, Yu Jeong; Kim, Seong Keun; Kim, Young Mi; Chae, Gue Tae; Jeong, Seong-Whan; Lee, Seong Beom

doi:10.1016/j.neulet.2009.06.011

Cited by 78 publications

(48 citation statements)

References 19 publications

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“…Reduced GSH status was reported in various diseases including a number of neurological disorders [15]. In our previous study, depletion of GSH with BSO significantly enhanced cytotoxicity by treatment of osteoblasts and glial cells with oxidative stresses [10,16].…”

Section: Discussionmentioning

confidence: 96%

GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition

Lee

Byun

Cho

et al. 2011

Korean J Physiol Pharmacol

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Golgi SNAP receptor complex 1 (GS28) has been implicated in vesicular transport between intra-Golgi networks and between endoplasmic reticulum (ER) and Golgi. Additional role(s) of GS28 within cells have not been well characterized. W e observed decreased expression of GS28 in rat ischemic hippocampus. In this study, we examined the role of GS28 and its molecular mechanisms in neuronal (SK-N-SH) cell death induced by hydrogen peroxide (H2O2). GS28 siRNA-transfected cells treated with H2O2 showed a significant increase in cytotoxicity under glutathione (GSH)-depleted conditions after pretreatment with buthionine sulfoximine, which corresponded to an increase of intracellular reactive oxygen species (ROS) in the cells. Pretreatment of GS28 siRNA-transfected cells with p38 chemical inhibitor significantly inhibited cytotoxicity; we also observed that p38 was activated in the cells by immunoblot analysis. W e confirmed the role of p38 MAPK in cotransfected cells with GS28 siRNA and p38 siRNA in the cell viability assay, flow cytometry, and immunoblot. Involvement of apoptotic or autophagic processes in the cells was not shown in the cell viability, flow cytometry, and immunoblot analyses. However, pretreatment of the cells with necrostatin-1 completely inhibited H2O2-induced cytotoxicity, ROS generation, and p38 activation, indicating that the cell death is necroptotic. Collectively these data imply that H2O2 induces necroptotic cell death in the GS28 siRNA-transfected cells and that the necroptotic signals are mediated by sequential activations in RIP1/p38/ROS. Taken together, these results indicate that GS28 has a protective role in H2O2-induced necroptosis via inhibition of p38 MAPK in GSH-depleted neuronal cells.

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Section: Discussionmentioning

confidence: 96%

GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition

Lee

Byun

Cho

et al. 2011

Korean J Physiol Pharmacol

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“…There may be cross-talk between the p53-sestrin-2 and HIF-1␣-BNIP3 signaling pathways. H 2 O 2 induces autophagic cell death via BNIP3-mediated suppression of the mTOR pathway in glioma cells (4) and activates BNIP3 through HIF-1␣ in neural cells (49). In macrophages, hypoxia upregulates sestrin-2 through HIF-1␣ and other mechanisms (14).…”

Section: Discussionmentioning

confidence: 99%

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

175

125

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Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1␣ and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stressinduced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1␣-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1␣-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.Bcl-2/adenovirus E1B 19 kDa-interacting protein-3; acute kidney injury; autophagy; mitophagy; sestrin-2 ISCHEMIA is the leading cause of acute kidney injury (AKI) in the adult population. Prominent morphological features of ischemic AKI include effacement and loss of the proximal tubule brush border, patchy loss of tubular cells, focal areas of proximal tubular dilation, and increased apoptosis (9). The mechanisms that dictate the survival or death of renal cells under oxidative stress must be more completely understood before novel therapeutic strategies for the treatment of ischemic AKI can be explored. Proximal renal tubular cells have high rates of ATP consumption and are very sensitive to hypoxia; thus, mitochondrial damage is one of the most important factors in determining the survival of these cells (1,43).Autophagy is one of the cellular processes that protect cells from genotoxic stress, oxidative stress, accumulation of misfolded proteins, and nutrient deprivation. We (20) have previously reported results from a study of autophagy in a mouse model of AKI. Autophagy plays roles in the pathogenesis of many diseases, and, in kidney disease, both beneficial and detrimental effects of autophagy have been reported (19 -22). Our understanding of autophagy has expanded greatly in recent years, largely due to the identification...

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“…87 Furthermore, mTOR can be inhibited by exogeneously added H 2 O 2 , 88,89 possibly mediated by BNIP3-upregulation. 89 H 2 O 2 treatment in Bax/Bak double-knockout MEFs, which induces necrotic cell death through the activation of Poly(ADP) ribose polymerase-1 (PARP-1) and depletion of cellular ATP content, leads to cytoprotective autophagy induction through the activation of AMPK and subsequent inhibition of mTOR (Fig. 2).…”

Section: Redox-regulation Of Autophagy Pathwaysmentioning

confidence: 99%

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Dewaele¹,

Maes²,

Agostinis³

2010

Autophagy

275

199

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Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway

Cited by 78 publications

References 19 publications

GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition

GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

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