HCT116 cells treated with the p97 inhibitior CB-5083
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73588 | GEO | 2015/11/09
SECONDARY ACCESSION(S): PRJNA297366
REPOSITORIES: GEO
Similar Datasets
Project description:The goal of this study was to analyze differential gene expression 8 hr after treatment of CB-5083, a small molecule inhibitor of p97 (VCP), in HCT116 cells grown in culture. DMSO treated cells were compared to cells treated with 1uM CB-5083 after 8 hr.
2015-11-09 | E-GEOD-73588 | biostudies-arrayexpress
Project description:To investigate the signaling patheway of VCP regulation PD-L1 in colorectal cancer cells, HCT116 cells were treated with CB-5083. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different cells CB-5083 treatment and untreatment.
2023-10-18 | GSE201778 | GEO
Project description:The goal was to determine the gene expression differences between CB-5083 and Bortezomib treated multiple myeloma cell lines Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis. CB-5083 decreases viability in MM cell lines and patient derived MM cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant MM models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with MM standard of care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several MM disease models and provide the rationale for clinical evaluation as monotherapy and in combination in MM.
2017-10-26 | GSE101923 | GEO
Project description:HCT116 cells treated with the p97 inhibitior CB-5083
| PRJNA297366 | ENA
Project description:Understanding how human coronavirus dysregulate host proteome during infection in human cells will identify general pathways that are common to coronavirus infection. NMS-873 is an allosteric p97/VCP ATPase inhibitor and was show to have antiviral effect in multiple viruses including SARS-CoV2. We first demonstrated that genetic knock down of p97 reduced HCoV-229E, HCoV-OC43 infection and secretion. To investigate how p97/VCP assists virus infection, we used unbiased quantitative proteomics to compare dysregulated proteomes caused by HCoV-229E, HCoV-OC43 and SARS-CoV2 infection. We then compared dysregulated proteomes after HCoV-229E and HCoV-OC43 infection with and without p97 knockdown. Moreover, we elucidated the impact of p97 on different stages of viral life cycle using two potent p97 inhibitors, CB-5083 and NMS-873 and demonstrate their can block HCoV replication. Together, our data provide insights to repurpose potential cancer drugs that target the essential host protein p97/VCP.
2021-11-03 | PXD026216 | Pride
Project description:The goal of this experiment is to identify differentially expressed genes between parental OVSAHO cells and CB-5083-resistant OVSAHO cells. Each group is treated with 5 microM CB-5083 for 6 hours and total RNA was extracted with Trizol. RNA sequencing library was performed using Illumina RNA library kit.
2018-11-02 | E-MTAB-7328 | biostudies-arrayexpress
Project description:ATP-competitive p97 inhibitor CB-5339, the successor of CB-5083, is being evaluated in Phase 1 clinical trials for anti-cancer therapy. Different modes of action p97 inhibitors such as allosteric inhibitors are useful to overcome one the major problems of targeted therapy: drug-induced resistance. We previously demonstrated allosteric p97 inhibitor NMS-873 can overcome CB-5083-induced resistance. Here, we found that NMS-873 but not CB-5083 affected glycometabolism. By establishing NMS-873-resistant cell lines and performing both cell-based and proteomic analysis, we confirmed that NMS-873 dysregulates glycometabolism in a p97-independent manner. We then used proteome integral solubility alteration with a temperature-based method (PISA T) to identify NDUFAF5 as one of the potential targets of NMS-873 in the mitochondrial complex I. Overall, we employed chemical proteomics and drug-induced thermal proteome changes to identify drug targets, in combination with drug-resistant cell lines to dissect on- and off-target effects. We also demonstrated that glycolysis inhibitor 2-DG enhanced the anti-proliferative effect of NMS-873. The polypharmacology of NMS-873 can be advantageous for anti-cancer therapy.
2022-05-19 | PXD025898 | Pride
Project description:Multiple Myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 forms a subcomplex of many chromatin remodeling complexes implicated in cancer progress. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt’s lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility.CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified ATF4/CEBP and E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB66-44 in MM cells, but experimental validation refuted this hypothesis.
2024-08-19 | GSE271840 | GEO
Project description:Multiple Myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 forms a subcomplex of many chromatin remodeling complexes implicated in cancer progress. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt’s lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility.CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified ATF4/CEBP and E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB66-44 in MM cells, but experimental validation refuted this hypothesis.
2024-08-19 | GSE271838 | GEO
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