Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response

Yokouchi, Makiko; Hiramatsu, Naoki; Hayakawa, Kunihiro; Kasai, Ayumi; Takano, Yosuke; Yao, Jian; Kitamura, Masanori

doi:10.1038/sj.cdd.4402154

Cited by 135 publications

(106 citation statements)

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“…32 In general, however, the PERK pathway is considered pro-survival, whereas the IRE1 pathway is regarded pro-apoptotic. 3,4,33 From this viewpoint, the pharmacological of 3 0 -deoxyadenosine should be advantageous for blockade of ER stress-induced cell injury. Indeed, we demonstrated in this report that in vivo administration with 3 0 -deoxyadenosine suppressed ER stress-induced activation of the IRE1-JNK pathway, induction of CHOP and consequent apoptosis in the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed as described before. 33 Primary antibodies used were anti-caspase-3 antibody, anti-phospho eIF2a (Ser51) antibody, anti-c-Jun antibody and anti-phospho c-Jun (Ser63) antibody from Cell Signaling (Beverly, MA, USA); and anti-PERK antibody, antiphospho PERK (Thr981) antibody, anti-eIF2a antibody and anti-ATF4 (CREB-2) antibody from Santa Cruz Biotechnology (Santa Cruz, CA, USA). As a loading control, levels of b-actin and lamin B1 were evaluated using anti-b-actin antibody (Sigma-Aldrich Japan) and anti-lamin B1 antibody (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

et al. 2011

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The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stressrelated disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3 0 -deoxyadenosine (cordycepin) towards cell survival. 3 0 -Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3 0 -Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2a signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2a, and dephosphorylation of eIF2a by salubrinal mimicked the anti-apoptotic effect of 3 0 -deoxyadenosine. Unexpectedly, although 3 0 -deoxyadenosine caused activation of eIF2a, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3 0 -deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3 0 -deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3 0 -deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders. Endoplasmic reticulum (ER) stress-mediated tissue injury is implicated in a wide range of pathologies including cancers, infection, atherosclerosis, ischemia, neurodegenerative disorders and metabolic diseases such as diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

et al. 2011

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“…28 In general, however, the PERK and the ATF6 pathways are considered pro-survival, whereas the IRE1 pathway is regarded pro-apoptotic. [29][30][31][32] A selective inhibitor of the IRE1 pathway should, therefore, have an advantage for the treatment of ER stress-related disorders. Indeed, in the present report, we showed that in vivo administration with rapamycin markedly suppressed ER stress-triggered activation of the IRE1-JNK pathway and consequent apoptosis in the kidney.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1–JNK pathway

et al. 2011

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Mammalian target of rapamycin (mTOR) has a key role in the regulation of an array of cellular function. We found that rapamycin, an inhibitor of mTOR complex 1 (mTORC1), attenuated endoplasmic reticulum (ER) stress-induced apoptosis. Among three major branches of the unfolded protein response, rapamycin selectively suppressed the IRE1-JNK signaling without affecting PERK and ATF6 pathways. ER stress rapidly induced activation of mTORC1, which was responsible for induction of the IRE1-JNK pathway and apoptosis. Activation of mTORC1 reduced Akt phosphorylation, which was an event upstream of IRE-JNK signaling and consequent apoptosis. In vivo, administration with rapamycin significantly suppressed renal tubular injury and apoptosis in tunicamycin-treated mice. It was associated with enhanced phosphorylation of Akt and suppression of JNK activity in the kidney. These results disclosed that, under ER stress conditions, mTORC1 causes apoptosis through suppression of Akt and consequent induction of the IRE1-JNK pathway.

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“…It has long been known that disruption of intracellular calcium homeostasis is one of the primary processes in the early development of cell injury [1][2][3] [19,[24][25][26][27][28]. In summary, ER homeostasis is a fragile equilibrium, which can be modulated by dysregulation of calcium or oxidative/reductive balance, features previously associated with oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells

Dejeans

Tajeddine

Beck

et al. 2010

Biochemical Pharmacology

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Please cite this article as: Dejeans N, Tajeddine N, Beck R, Verrax J, Taper H, Gailly P, Calderon PB, Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells, Biochemical Pharmacology (2008), doi:10.1016/j.bcp.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 2 ABSTRACTIncrease in cytosolic calcium concentration ([Ca 2+ ] c ), release of endoplasmic reticulum (ER) calcium ([Ca 2+ ] er ) and ER stress have been proposed to be involved in oxidative toxicity.Nevertheless, their relative involvements in the processes leading to cell death are not well defined. In this study, we investigated whether oxidative stress generated during ascorbatedriven menadione redox cycling (Asc/Men) could trigger these three events, and, if so, A c c e p t e d M a n u s c r i p t 3 IntroductionIt has long been known that disruption of intracellular calcium homeostasis is one of the primary processes in the early development of cell injury [1][2][3] [19,[24][25][26][27][28]. In summary, ER homeostasis is a fragile equilibrium, which can be modulated by dysregulation of calcium or oxidative/reductive balance, features previously associated with oxidative stress. However, studies of the links between these factors are scarce.We and others have shown that the association of ascorbate and menadione is an H 2 O 2 -generating system that results in necrosis-like cell death in a wide variety of cancer cell types [29][30][31][32][33][34][35] including MCF-7 cells (a human breast derived cell line), and that loss of calcium homeostasis appeared to be a major factor in the cytotoxicity [36]. The aim of the present study was to investigate the role of disruption of calcium homeostasis and a potential involvement of ER stress in the mechanisms leading to cancer cell death from an oxidative Materials and methods ChemicalsMenadione sodium bisulfite (Men), sodium ascorbate ( Cell Culture and TreatmentsThe MCF-7 cell line was a gift from Dr. F. Brasseur (Ludwig Institute for Cancer Research, LICR-Brussels). The cells were cultured in DMEM (Dulbecco's modified eagle medium, (Gibco BRL, Life Technologies, Merelbeke, BE)) supplemented with 10% fetal calf serum, penicillin (10 000 U/ml), streptomycin (10 mg/ml) and 1.2% glutamine. The cultures were maintained at a density of about 50x10³ cells/cm². The medium was changed at 48-72 h intervals. All cultures were maintained at 37°C in 95% air/5% CO2 with 100% humidity. minutes before the addition of ascorbate and menadione. Cells were incubated with TG or iodoacetate at concentration...

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Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response

Cited by 135 publications

References 40 publications

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1–JNK pathway

Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells

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