Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells

Zhang, Lin Jie; Chen, Si; Wu, Pin Jou; Hu, Chunsong; Thorne, Rick F.; Luo, Cunjin; Hersey, Peter; Zhang, Xu Dong

doi:10.1016/j.canlet.2008.08.030

Cited by 52 publications

(36 citation statements)

References 24 publications

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“…It has been demonstrated previously that induction of ER stress activates MEK/ERK signaling in various cell types, although it is largely a survival mechanism (55)(56)(57)(58)(59). In our cell systems, tunicamycin and thapsigargin also increased ERK1/2 and RSK phosphorylation (supplemental Fig.…”

Section: Discussionsupporting

confidence: 64%

ERK/Ribosomal S6 Kinase (RSK) Signaling Positively Regulates Death Receptor 5 Expression through Co-activation of CHOP and Elk1

Liu

Yue

et al. 2010

Journal of Biological Chemistry

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Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers apoptosis upon binding to its ligand or when overexpressed. Its expression is induced by certain small molecule drugs, including celecoxib, through mechanisms that have not been fully elucidated. The current study has revealed a novel ERK/ribosomal S6 kinase (RSK)-dependent mechanism that regulates DR5 expression primarily using celecoxib as a DR5 inducer. Both C/EBP homologous protein (CHOP) and Elk1 are required for celecoxib-induced DR5 expression based on promoter deletion and mutation analysis and siRNA-mediated gene silencing results. Co-expression of both CHOP and Elk1 exhibited enhanced effects on increasing DR5 promoter activity and DR5 expression, indicating that CHOP and Elk1 co-operatively regulate DR5 expression. Because Elk1 is an ERK-regulated protein, we accordingly found that celecoxib increased the levels of phosphorylated ERK1/2, RSK2, and Elk1. Inhibition of either ERK signaling with a MEK inhibitor or ERK1/2 siRNA, or RSK2 signaling with an RSK2 inhibitor or RSK2 siRNA abrogated DR5 up-regulation by celecoxib as well as other agents. Moreover, these inhibitions suppressed celecoxib-induced CHOP up-regulation. Thus, ERK/RSK-dependent, CHOP and Elk1-mediated mechanisms are critical for DR5 induction. Additionally, celecoxib increased CHOP promoter activity in an ATF4-dependent manner, and siRNA-mediated blockade of ATF4 abrogated both CHOP induction and DR5 up-regulation, indicating that ATF4 is involved in celecoxib-induced CHOP and DR5 expression. Collectively, we conclude that small molecules such as celecoxib induce DR5 expression through activating ERK/RSK signaling and subsequent Elk1 activation and ATF4-dependent CHOP induction. Death receptor 5 (DR54 ; also called TRAIL-R2 or killer/ DR5) is a cell surface receptor for the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). It becomes oligomerized (trimerized) upon binding to its ligand TRAIL (or upon overexpression) and then transmits an apoptotic signal through rapid activation of caspase-8-dependent caspase cascades. This process involves trimerized DR5 interacting specifically with the adaptor protein Fas-associated death domain via death domain interaction and subsequent recruitment of caspase-8 through the death effector domain between Fas-associated death domain and caspase-8, leading to caspase-8 activation and ultimate apoptosis (1).

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Section: Discussionsupporting

confidence: 64%

ERK/Ribosomal S6 Kinase (RSK) Signaling Positively Regulates Death Receptor 5 Expression through Co-activation of CHOP and Elk1

Liu

Yue

et al. 2010

Journal of Biological Chemistry

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“…50 To this end, rapid activation of ERK1/2 is required to mediate the upregulation of GRP78 by ER stress. 51 It is therefore speculated that proteasome inhibition may activate ERK1/2 through induction of ER stress. In our hands, MEK inhibitor aggravates the antiproliferative effect of MG-132, suggesting that phosphorylation of ERK1/2 serves as an autoregulatory mechanism to counteract the antiproliferative effect of proteasome inhibition.…”

Section: Discussionmentioning

confidence: 99%

Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells

Cho²,

Lee³

et al. 2010

Autophagy

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“…Our results showed that JNK and p38 activation persisted with increased ER stress, while ERK activation was attenuated early in HeLa cells undergoing prolonged exposure to DTT. In gastric cancer cells, MEK inhibition blocked Grp78 upregulation and enhanced apoptosis induced by ER stress (8). Our results showed that JNK/p38 inhibition attenuated DTT-induced cytotoxity while ERK inhibition promoted DTT-induced cell death.…”

Section: Discussionmentioning

confidence: 50%

“…Sustained activation of JNK and p38 is dependent on apoptosis signaling regulating kinase 1 (ASK1), a molecule implicated in the apoptosis mediated by ER stress (7). Inhibition of MEK blocks glucose-regulated protein-78 (GRP78) upregulation and enhances apoptosis induced by ER stress in gastric cancer cells (8). In another study, the ER stress response modulated the balance between ERK and JNK signaling pathways to prevent cell death after oxidative injury (9).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagic flux by ROS promotes apoptosis during DTT-induced ER/oxidative stress in HeLa cells

Xiang

Yang

et al. 2016

Oncology Reports

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Abstract. As targets for cancer therapy, endoplasmic reticulum (ER) stress and autophagy are closely linked. However, the signaling pathways responsible for induction of autophagy in response to ER stress and its cellular consequences appear to vary with cell type and stimulus. In the present study, we showed that dithiothreitol (DTT) induced ER stress in HeLa cells in a time-and dose-dependent fashion. With increased ER stress, reactive oxygen species (ROS) production increased and autophagy flux, assessed by intracellular accumulation of LC3B-II and p62, was inhibited. N-acetyl-L-cysteine (NAC), a classic antioxidant, exacerbated cell death induced by 3.2 mM of DTT, but attenuated that induced by 6.4 mM DTT. Low cytotoxic doses of DTT transiently activated c-JNU N-terminal kinase (JNK) and p38, whereas high dose of DTT persistently activated JNK and p38 and simultaneously reduced extracellular signal-regulated kinase (ERK) activity. Combined treatment with DTT and U0126, an inhibitor of ERK upstream activators mitogen-activated protein kinase (MAPK) kinase 1 and 2 (MEK1/2), blocked autophagy flux in HeLa cells. This effect was similar to that caused by a combination of DTT and chloroquine (CQ). These data suggested that insufficient autophagy was accompanied by increased ROS production during DTT-induced ER stress. ROS appeared to regulate MAPK signaling, switching from a pro-survival to a pro-apoptotic signal as ER stress increased. ERK inhibition by ROS during severe ER stress blocked autophagic flux. Impaired autophagic flux, in turn, aggravated ER stress, ultimately leading to cell death. Taken together, our data provide the first reported evidence that ROS may control cell fate through regulating the MAPK pathways and autophagic flux during DTT-induced ER/oxidative stress.

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Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells

Cited by 52 publications

References 24 publications

ERK/Ribosomal S6 Kinase (RSK) Signaling Positively Regulates Death Receptor 5 Expression through Co-activation of CHOP and Elk1

ERK/Ribosomal S6 Kinase (RSK) Signaling Positively Regulates Death Receptor 5 Expression through Co-activation of CHOP and Elk1

Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells

Inhibition of autophagic flux by ROS promotes apoptosis during DTT-induced ER/oxidative stress in HeLa cells

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