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The ERAD inhibitor Eeyarestatin I is a bifunctional compound with an ER localizing domain and a p97/VCP inhibitory group

ABSTRACT: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death for cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib. Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23849 | GEO | 2010/11/24

SECONDARY ACCESSION(S): PRJNA130671

REPOSITORIES: GEO

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The ERAD inhibitor Eeyarestatin I is a bifunctional compound with an ER localizing domain and a p97/VCP inhibitory group

Project description:Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death for cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib. Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapy. Cells were treated with EerI, CBU-028, or 5-NA each at 10uM in duplicates for 10h

2010-11-24 | E-GEOD-23849 | biostudies-arrayexpress

ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells

Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.

2009-02-20 | GSE14003 | GEO

Transcription profiling of human cell cancer line treated with bortezomib or Eeyarestatin I (EerI) reveals ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells

2009-02-28 | E-GEOD-14003 | biostudies-arrayexpress

Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

Project description:Sel1L is an adaptor protein for the E3 ligase Hrd1 involved in endoplasmic reticulum-associated degradation (ERAD). Its physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we provide the first in vivo evidence that Sel1L is indispensable for Hrd1 stability, ER homeostasis and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 weeks with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation and promotes cell death. Serendipitously, using biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of mammalian ERAD and ER homeostasis, which is essential for protein translation, pancreatic function, cellular and organismal survival. Pancreas tissue of wild type and inducible Sel1L knockout mice were subjected to gene expression analysis.

2013-12-04 | E-GEOD-52929 | biostudies-arrayexpress

Sel1L is Indispensable for Mammalian ERAD, ER Homeostasis and Survival

2013-12-04 | GSE52929 | GEO

ChIP-Seq of TRIB3 and ATF4 in HepG2 cells treated with bortezomib

Project description:The proteasome is an appealing anti-cancer drug target and the proteasome inhibitor bortezomib has been approved for the treatment of certain types of malignancies. However, the molecular mechanisms underlying cancer cell resistance to bortezomib remain poorly understood. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. To map genome-wide chromatin binding loci of TRIB3 protein, we fused a Flag tag to endogenous TRIB3 in HepG2 cells and performed ChIP-Seq. The results demonstrate that TRIB3 predominantly colocalizes with ATF4 on chromatin and the proteins reside in genomic regions containing the C/EBP-ATF motif. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP-ATF-driven transcription, augments ER stress and cell death in cells exposed to bortezomib, while TRIB3 overexpression enhances the cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2alpha-ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib.

2021-05-24 | GSE166958 | GEO

ASPSCR1-TFE3 reprograms transcription by organizing enhancers around hexameric VCP [ASPS1 VCP ChIP]

Project description:Aberrant transcription in alveolar soft part sarcoma (ASPS) is orchestrated by the fusion oncoprotein, ASPSCR1-TFE3, product of a gene fusion created by a t(X;17) chromosomal translocation. Here, proteomics of proteins co-immunoprecipitating with ASPSCR1-TFE3 revealed strong enrichment of VCP/p97, an AAA+ ATPase with known segregase function. Positive and negative genetic experiments with ASPSCR1-TFE3 and VCP demonstrated that they function co-dependently for cancer cell proliferation, colony formation, enhancer activation, chromatin conformation, and transcription

2023-01-01 | GSE162727 | GEO

Gene expression profiling of HepG2 cell response to bortezomib in combination with nelfinavir or ISRIB, compounds targeting the eIF2a-ATF4 pathway

Project description:We investigate how modulation of the eIF2alpha-ATF4 stress pathway affects hepatoma cell response to bortezomib. Transcriptome profiling revealed that many ATF4 transcriptional target genes are among the highest upregulated genes in bortezomib-treated HepG2 human hepatoma cells. While pharmacological enhancement of the eIF2alpha-ATF4 pathway activity results in the elevation of the activities of all branches of the unfolded protein response (UPR) and sensitizes cells to bortezomib toxicity, the suppression of ATF4 induction delays bortezomib-induced cell death. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP-ATF-driven transcription, augments ER stress and cell death in cells exposed to bortezomib, while TRIB3 overexpression enhances the cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2alpha-ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib.

2021-05-24 | GSE166923 | GEO

p97/VCP inhibition radiosensitises cancer cells through excessive MRE11-dependent DNA end resection

Project description:Cancer cells are under constant proteotoxic stress and have an increased genomic instability. They therefore rely on upregulation of protein homeostasis and the DNA damage response (DDR) for survival. The ubiquitin-dependent ATPase p97 is a central component of the ubiquitin-proteasome degradation system (UPS), involved in both protein homeostasis and DDR. p97 is overexpressed in many tumours and its overexpression correlates with poor prognosis in patients. To explore the concept of cancer cell killing by combined targeting of DDR and proteostasis, we induced DNA damage by ionising radiation (IR) and inhibited proteostasis by CB-5083, a specific small molecule inhibitor of p97, in bladder cancer cell lines and a mouse xenograft model. Combined therapy induced radiosensitivity and supressed xenograft tumour growth. Mechanistically, inactivation of the p97 ATPase activity results in proteotoxic accumulation of the nuclease MRE11 at the sites of IR-induced DNA lesions. This leads to excessive formation of single-stranded DNA (ssDNA), inhibition of HR, reliance on SSA for DSB repair and synthetic lethality after IR exposure in non-homologous end-joining-defective tumour cells such as those in muscle-invasive bladder carcinoma patients

2021-05-18 | PXD016279 | Pride

The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group.

Project description:BackgroundProtein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib.Methodology and principal findingsHere we developed in vitro binding and cell-based functional assays to demonstrate that a nitrofuran-containing (NFC) group in EerI is the functional domain responsible for the cytotoxicity. Using both SPR and pull down assays, we show that EerI directly binds the p97 ATPase, an essential component of the ERAD machinery, via the NFC domain. An aromatic domain in EerI, although not required for p97 interaction, can localize EerI to the ER membrane, which improves its target specificity. Substitution of the aromatic module with another benzene-containing domain that maintains membrane localization generates a structurally distinct compound that nonetheless has similar biologic activities as EerI.Conclusions and significanceOur findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and to induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapeutics.

| S-EPMC2993181 | biostudies-literature

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