Activated ERBB2/HER2 Licenses Sensitivity to Apoptosis upon Endoplasmic Reticulum Stress through a PERK-Dependent Pathway

Martín-Pérez, Rosa; Palacios, Carmen; Yerbes, Rosario; Cano-González, Ana; Iglesias-Serret, Daniel; Gil, Joan; Reginato, Mauricio J.; López‐Rivas, Abelardo

doi:10.1158/0008-5472.can-13-1747

Cited by 57 publications

(85 citation statements)

References 52 publications

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“…Importantly, the authors seem focused to disprove one study, while ignoring numerous studies that have shown a role of DR5 and caspase-8 in apoptosis activated by different UPR-inducing stimuli such as thapsigargin or glucose deprivation 3,8,9 , Altogether, these data indicate that DR5, caspase-8, Bim, Bid and Noxa are required for ER stress and UPR-mediated death in a cell type-dependent manner. …”

Section: Correspondencementioning

confidence: 96%

A role for caspase-8 and TRAIL-R2/DR5 in ER-stress-induced apoptosis

Muñoz-Pinedo

López‐Rivas

2017

Cell Death Differ

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Section: Correspondencementioning

confidence: 96%

A role for caspase-8 and TRAIL-R2/DR5 in ER-stress-induced apoptosis

Muñoz-Pinedo

López‐Rivas

2017

Cell Death Differ

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“…(HER2/Neu) sensitizes human breast epithelial cells to thapsigargin treatment resulting on cell death due to an altered unfolded protein response [60]. Mutant ERBB2 triggers a deregulation of ERK, AKT and the mTOR pathway which results in UPR-dependent apoptosis in those cell lines.…”

Section: Author Manuscriptmentioning

confidence: 99%

Cell death induced by endoplasmic reticulum stress

2015

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The endoplasmic reticulum (ER) is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occur in this organelle. Many Author ManuscriptThis article is protected by copyright. All rights reserved conditions that impose stress to the cells, including hypoxia, starvation, infections and changes in secretory needs challenge the folding capacity of the cell and promote ER stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim to restore homeostasis. This is known as the Unfolded Protein Response (UPR), which also intersects with the Integrated Stress Response (ISR) that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the UPR are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as JNK and the downstream transcription factors XBP-1, ATF4 and CHOP. These proteins aim to restore homeostasis but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. Additionally, ER stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of Caspase-8.ER stress is a common feature in the pathology of numerous diseases as it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to ER stress can accelerate discovery of drugs against these diseases. KeywordsEndoplasmic reticulum stress The endoplasmic reticulum and the Unfolded Protein Response sensorsThe endoplasmic reticulum (ER) is the organelle where transmembrane proteins and proteins that are going to be secreted are synthesized and folded. This organelle, however, is essential for multiple other cellular functions such as Ca 2+ buffering, biosynthesis of phospholipids and cholesterol. Synthesis of proteins, cholesterol and some metabolites is an ATP demanding process that also requires the right ionic strength. Disturbances in many homeostatic processes will thus lead to a state in which protein folding slows down (ER stress). The subsequent accumulation of misfolded or unfolded proteins will indicate problems in cellular homeostasis that frequently end up in cell death.Problems in protein folding can occur due to stressors apparently disparate such as starvation or viral infection. These stimuli promote the activation of a series of signals that promote synthesis of new proteins to cope with stress while reducing general protein synthesis [1,2]. This is called the Unfolded Protein Response (UPR). Another way by which the UPR aims to restore homeostasis is the stimulation of protein degradation via autophagy and the enhanced clearance of unfolded proteins by a process termed ER-Associated Degradation (ERAD).The UPR is orchestrated by three main sensors that reside in the membrane of the ER. These transmembrane proteins bind to the chaperone GRP78/BiP in the...

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“…Human ESCC cell lines EC1, EC109, Kyse450, Kyse30, and Kyse510 were routinely cultured in Dulbecco's Modified Eagle's Medium (Hyclone), containing 10% FBS (Biochrom, AG) and 1% penicillin-streptomycin solution, at 37 C with 5% CO 2 . MLN4924 was synthesized and prepared as previously described (3,25,26).…”

Section: Cell Lines Culture and Reagentsmentioning

confidence: 99%

“…Previous studies demonstrated that activating transcription factor 4 (ATF4) serves as a substrate of CRL/SCF bTrcp ubiquitin ligase (21,34,35), and transcription factor CHOP, a classical downstream target of ATF4, can regulate the transactivation of DR5 (36)(37)(38). Based on this, we hypothesized that MLN4924 may induce ATF4 accumulation due to the inactivation of CRL/ SCF bTrcp ubiquitin ligase which requires nedd8 conjugation to its essential subunit cullins for activation, and therefore transactivates CHOP and DR5 to activate extrinsic apoptosis.…”

Section: Dr5 Is Transactivated By Activating Transcription Factor 4/cmentioning

confidence: 99%

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Chen

Liang

et al. 2016

Clinical Cancer Research

106

102

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Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined.Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies.Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)-mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival.Conclusions: Our findings highlight a critical role of ATF4-CHOP-DR5 axis-mediated extrinsic apoptosis in neddylationtargeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation.

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Activated ERBB2/HER2 Licenses Sensitivity to Apoptosis upon Endoplasmic Reticulum Stress through a PERK-Dependent Pathway

Cited by 57 publications

References 52 publications

A role for caspase-8 and TRAIL-R2/DR5 in ER-stress-induced apoptosis

A role for caspase-8 and TRAIL-R2/DR5 in ER-stress-induced apoptosis

Cell death induced by endoplasmic reticulum stress

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

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