Salubrinal Protects Against Cigarette Smoke Extract-induced HBEpC Apoptosis Likely Via Regulating the Activity of PERK-eIF2α Signaling Pathway

Tan, Yuan; Luo, Bailing; Wei, Tianhong; Zhang, Li; He, Ben; Niu, Ruichao

doi:10.1016/j.arcmed.2012.10.002

Cited by 36 publications

(27 citation statements)

References 21 publications

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“…This is further supported by our previous studies using another protein synthesis inhibitor, salubrinal, to control Ub accumulation (14,73). Salubrinal inhibits protein synthesis by preventing dephosphorylation to eukaryotic translation initiation factor (eIF) 2a to stabilize phospho-eIF2a (73,74), which inhibits initiation of translation during protein synthesis. Furthermore, a previous study compared the relative effects of CHX and CSE treatments on protein synthesis, but lacked cotreatment (CSE 1 CHX) and quantification of protein aggregation (aggresomes) (33).…”

Section: Copdemphysema Pathogenesissupporting

confidence: 59%

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Tran

et al. 2015

Am J Respir Cell Mol Biol

121

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Cigarette smoke (CS) exposure is known to induce proteostasis imbalance that can initiate accumulation of ubiquitinated proteins. Therefore, the primary goal of this study was to determine if first-and secondhand CS induces localization of ubiquitinated proteins in perinuclear spaces as aggresome bodies. Furthermore, we sought to determine the mechanism by which smoke-induced aggresome formation contributes to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Hence, Beas2b cells were treated with CS extract (CSE) for in vitro experimental analysis of CSinduced aggresome formation by immunoblotting, microscopy, and reporter assays, whereas chronic CS-exposed murine model and human COPD-emphysema lung tissues were used for validation. In preliminary analysis, we observed a significant (P , 0.01) increase in ubiquitinated protein aggregation in the insoluble protein fraction of CSE-treated Beas2b cells. We verified that CS-induced ubiquitin aggregrates are localized in the perinuclear spaces as aggresome bodies. These CS-induced aggresomes (P , 0.001) colocalize with autophagy protein microtubule-associated protein 1 light chain-3B 1 autophagy bodies, whereas U.S. Food and Drug Administration-approved autophagy-inducing drug (carbamazepine) significantly (P , 0.01) decreases their colocalization and expression, suggesting CS-impaired autophagy. Moreover, CSE treatment significantly increases valosin-containing protein-p62 protein-protein interaction (P , 0.0005) and p62 expression (aberrant autophagy marker; P , 0.0001), verifying CSimpaired autophagy as an aggresome formation mechanism. We also found that inhibiting protein synthesis by cycloheximide does not deplete CS-induced ubiquitinated protein aggregates, suggesting the role of CS-induced protein synthesis in aggresome formation. Next, we used an emphysema murine model to verify that chronic CS significantly (P , 0.0005) induces aggresome formation. Moreover, we observed that autophagy induction by carbamazepine inhibits CS-induced aggresome formation and alveolar space enlargement (P , 0.001), confirming involvement of aggresome bodies in COPD-emphysema pathogenesis. Finally, significantly higher p62 accumulation in smokers and severe COPD-emphysema lungs (Global Initiative for Chronic Obstructive Lung Disease Stage III/IV) as compared with normal nonsmokers (Global Initiative for Chronic Obstructive Lung Disease Stage 0) substantiates the pathogenic role of autophagy impairment in aggresome formation and COPD-emphysema progression. In conclusion, CS-induced aggresome formation is a novel mechanism involved in COPD-emphysema pathogenesis.Keywords: cigarette smoke; chronic obstructive pulmonary disease; ubiquitin; aggresomes; autophagy Clinical RelevanceWe anticipate that these research findings will have a great impact on development of novel therapeutics for treatment of chronic obstructive pulmonary disease-emphysema and other diseases involving impaired proteostasis or autophagy. In addition to the therapeutic application, thes...

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Section: Copdemphysema Pathogenesissupporting

confidence: 59%

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Tran

et al. 2015

Am J Respir Cell Mol Biol

121

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“…Several studies also revealed that eIF2α could be phosphorylated by thapsigargin and tunicamycin3536, which in turn enhanced the lethal effect when suspension-activated PERK35. Recent reports demonstrated that the persistent PERK signaling protected cells from anoikis37, and the intact PERK-eIF2α pathway could defense against cigarette smoke extract insult in HBE cells38. These studies further supported our findings that the PERK-eIF2α pathway is crucial for hepatocyte cell survival under the exposure of bystander signals.…”

Section: Discussionsupporting

confidence: 89%

Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells

Xie

Zhang

et al. 2016

Sci Rep

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Radiation-induced bystander effect (RIBE) has important implications for secondary cancer risk assessment during cancer radiotherapy, but the defense and self-protective mechanisms of bystander normal cells are still largely unclear. The present study found that micronuclei (MN) formation could be induced in the non-irradiated HL-7702 hepatocyte cells after being treated with the conditioned medium from irradiated hepatoma HepG2 cells under either normoxia or hypoxia, where the ratio of the yield of bystander MN induction to the yield of radiation-induced MN formation under hypoxia was much higher than that of normoxia. Nonetheless, thapsigargin induced endoplasmic reticulum (ER) stress and dramatically suppressed this bystander response manifested as the decrease of MN and apoptosis inductions. Meanwhile, the interference of BiP gene, a major ER chaperone, amplified the detrimental RIBE. More precisely, thapsigargin provoked ER sensor of PERK to initiate an instantaneous and moderate ER stress thus defensed the hazard form RIBE, while BiP depletion lead to persistently destroyed homeostasis of ER and exacerbated cell injury. These findings provide new insights that the mild ER stress through BiP-PERK-p-eIF2α signaling pathway has a profound role in protecting cellular damage from RIBE and hence may decrease the potential secondary cancer risk after cancer radiotherapy.

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“…ER stress has been reported to induce apoptosis in various cell types via the upregulation of protein translation mediated through the PERK-eIF2α pathway (24)(25)(26)(27). For instance, upon ER stress, the ER chaperone GRP78 dissociates from the PERK and initiates transphosphorylation with subsequent activation of the kinase (28).…”

Section: Discussionmentioning

confidence: 99%

PCSK9 regulates apoptosis in human lung adenocarcinoma A549 cells via endoplasmic reticulum stress and mitochondrial signaling pathways

Cui

Cao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilisin family of PCs that encodes a neural apoptosis-regulated convertase 1. However, the precise role of PCSK9 in lung cancer cell apoptosis has remained elusive. In the present study, A549 human lung adenocarcinoma cells were transfected with PCSK9 small interfering (si)RNA to investigate the underlying mechanisms of apoptosis. The results indicated that PCSK9 siRNA exhibited anti-tumor activity by inducing apoptosis as determined by a Cell Counting Kit-8 and Hoechst staining analysis. In addition, PCSK9 siRNA significantly increased apoptosis of A549 cells in part via activation of caspase-3 and downregulation of the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis protein. Moreover, the results demonstrated that perturbations in the mitochondrial membrane were associated with the deregulation of the Bax/Bcl-2 ratio, which led to the release of cytochrome c after PCSK9 siRNA transfection. In addition, PCSK9 siRNA also induced endoplasmic reticulum stress (ERS) by increasing the levels of 78 kDa glucose-regulated protein (GRP78), GRP94, phosphorylated protein kinase R-like ER kinase and phosphorylated eukaryotic initiation factor 2α. Therefore, these results demonstrated that PCSK9 siRNA may exert its anti-tumor activity through inducing mitochondrial dysfunction and ERS-associated cell death in A549 cells.

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Salubrinal Protects Against Cigarette Smoke Extract-induced HBEpC Apoptosis Likely Via Regulating the Activity of PERK-eIF2α Signaling Pathway

Cited by 36 publications

References 21 publications

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells

PCSK9 regulates apoptosis in human lung adenocarcinoma A549 cells via endoplasmic reticulum stress and mitochondrial signaling pathways

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