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Omics score: 65

Multiplexed proteome dynamics profiling of HSP90 inhibitor 17-AAG

ABSTRACT: Investigation of proteostatic effects of HSP90 inhibition by 17-AAG and differentiation of maturation state dependent HSP90 requirements of proteins.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Homo sapiens

TISSUE(S): Tissue Not Applicable To Dataset

DISEASE(S): Not Available

SUBMITTER: Maria Faelth Savitski

LAB HEAD: Marcus Bantscheff

PROVIDER: PXD008633 | Pride | 2018-04-05

REPOSITORIES: Pride

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	0231_F1_R1_P73995B01_TMT8.raw.gz	Raw
	0231_F1_R1_P73995B02_TMT8.raw.gz	Raw
	0231_F1_R1_P73995B03_TMT8.raw.gz	Raw
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Publications

Multiplexed Proteome Dynamics Profiling Reveals Mechanisms Controlling Protein Homeostasis.

Savitski Mikhail M MM Zinn Nico N Faelth-Savitski Maria M Poeckel Daniel D Gade Stephan S Becher Isabelle I Muelbaier Marcel M Wagner Anne J AJ Strohmer Katrin K Werner Thilo T Melchert Stephanie S Petretich Massimo M Rutkowska Anna A Vappiani Johanna J Franken Holger H Steidel Michael M Sweetman Gavain M GM Gilan Omer O Lam Enid Y N EYN Dawson Mark A MA Prinjha Rab K RK Grandi Paola P Bergamini Giovanna G Bantscheff Marcus M

Cell 20180315 1

Protein degradation plays important roles in biological processes and is tightly regulated. Further, targeted proteolysis is an emerging research tool and therapeutic strategy. However, proteome-wide technologies to investigate the causes and consequences of protein degradation in biological systems are lacking. We developed "multiplexed proteome dynamics profiling" (mPDP), a mass-spectrometry-based approach combining dynamic-SILAC labeling with isobaric mass tagging for multiplexed analysis of ...[more]

PMID: 29551266

Similar Datasets

Multiplexed proteome dynamics profiling of HSP90 inhibitor 17-AAG in T-cells

Project description:Investigation of proteostatic effects of HSP90 inhibition by 17-AAG and differentiation of maturation state dependent HSP90 requirements of proteins in resting T-cells.

2018-05-02 | PXD008635 | Pride

Multiplexed proteome dynamics profiling of HSP90 inhibitor 17-AAG in anti-CD3 and anti-CD28 stimulated T-cells

Project description:Investigation of proteostatic effects of HSP90 inhibition by 17-AAG and differentiation of maturation state dependent HSP90 requirements of proteins in activated T-cells.

2018-05-02 | PXD008634 | Pride

Expression profiling of HSP90 inhibitor 17-AAG in anti-CD3 and anti-CD28 stimulated T-cells

Project description:Investigation of expression effects of HSP90 inhibition by 17-AAG of proteins in resting and activated T-cells.

2018-05-02 | PXD008627 | Pride

Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

Project description:Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination. There are 12 samples in total. There are three experimental replicate. Samples 1, 5 and 9 are control (C) (untreated PC3- prostate cancer cells). Samples 2, 6, and 10 are cells treated with Wee1 inhibitor II (W). Samples 3, 7, and 11 are treated with 17-AAG (A), (an Hsp90 inhibitor). Samples 4, 8, and 12 are treated with both Wee1 inhibitorII and 17-AAG (WA). Samples 5 was removed from our analysis due to weak signal.

2013-01-10 | E-GEOD-38972 | ArrayExpress

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.

Project description:Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.

1000-01-01 | S-EPMC1635022 | BioStudies

Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin inhibits the proliferation of ARPE-19 cells.

Project description:BACKGROUND: The antiproliferative effect of the Hsp90 inhibitor 17-AAG (17-allylamino-17-demethoxygeldanamycin) on human retinal pigment epithelial cells is investigated. METHODS: MTT and flow cytometry were used to study the antiproliferative effects of the 17-AAG treatment of ARPE-19 cells. 2D gel electrophoresis (2-DE) and mass spectrometry were applied to detect the altered expression of proteins, which was verified by real-time PCR. Gene Ontology analysis and Ingenuity Pathway Analysis (IPA) were utilized to analyze the signaling pathways, cellular location, function, and network connections of the identified proteins. And SOD assay was employed to confirm the analysis. RESULTS: 17-AAG suppressed the proliferation of ARPE-19 cells by inducing cell cycle arrest and apoptosis. Proteomic analysis revealed that the expression of 94 proteins was altered by a factor of more than 1.5 following exposure to 17-AAG. Of these 94, 87 proteins were identified. Real-time PCR results indicated that Hsp90 and Hsp70, which were not identified by proteomic analysis, were both upregulated upon 17-AAG treatment. IPA revealed that most of the proteins have functions that are related to oxidative stress, as verified by SOD assay, while canonical pathway analysis revealed glycolysis/gluconeogenesis. CONCLUSIONS: 17-AAG suppressed the proliferation of ARPE-19 cells by inducing cell cycle arrest and apoptosis, and possibly by oxidative stress.

2010-01-01 | S-EPMC2873497 | BioStudies

Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer.

Project description:Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.

1000-01-01 | S-EPMC5432248 | BioStudies

Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells.

Project description:Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG-resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC(50)/parental line IC(50)) of 20 to 137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQO1) expression/activity and 17-AAG IC(50) was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors.

2009-01-01 | S-EPMC2652695 | BioStudies

Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX.

Project description:Inhibitors of the molecular chaperone heat shock protein 90 (HSP90) are of considerable current interest as targeted cancer therapeutic agents because of the ability to destabilize multiple oncogenic client proteins. Despite their resulting pleiotropic effects on multiple oncogenic pathways and hallmark traits of cancer, resistance to HSP90 inhibitors is possible and their ability to induce apoptosis is less than might be expected. Using an isogenic model for BAX knockout in HCT116 human colon carcinoma cells, we demonstrate the induction of BAX-dependent apoptosis at pharmacologically relevant concentrations of the HSP90 inhibitor 17-AAG both in vitro and in tumor xenografts in vivo. Removal of BAX expression by homologous recombination reduces apoptosis in vitro and in vivo but allows a lower level of cell death via a predominantly necrotic mechanism. Despite reducing apoptosis, the loss of BAX does not alter the overall sensitivity to 17-AAG in vitro or in vivo. The results indicate that 17-AAG acts predominantly to cause a cytostatic antiproliferative effect rather than cell death and further suggest that BAX status may not alter the overall clinical response to HSP90 inhibitors. Other agents may be required in combination to enhance tumor-selective killing by these promising drugs. In addition, there are implications for the use of apoptotic endpoints in the assessment of the activity of molecularly targeted agents.

1000-01-01 | S-EPMC3875762 | BioStudies

NAD(P)H:Quinone Oxidoreductase-1 Expression Sensitizes Malignant Melanoma Cells to the HSP90 Inhibitor 17-AAG.

Project description:The KEAP1-NRF2 pathway regulates cellular redox homeostasis by transcriptional induction of genes associated with antioxidant synthesis and detoxification in response to oxidative stress. Previously, we reported that KEAP1 mutation elicits constitutive NRF2 activation and resistance to cisplatin (CDDP) and dacarbazine (DTIC) in human melanomas. The present study was conducted to clarify whether an HSP90 inhibitor, 17-AAG, efficiently eliminates melanoma with KEAP1 mutation, as the NRF2 target gene, NQO1, is a key enzyme in 17-AAG bioactivation. In melanoma and non-small cell lung carcinoma cell lines with or without KEAP1 mutations, NQO1 expression and 17-AAG sensitivity are inversely correlated. NQO1 is highly expressed in normal melanocytes and in several melanoma cell lines despite the presence of wild-type KEAP1, and the NQO1 expression is dependent on NRF2 activation. Because either CDDP or DTIC produces reactive oxygen species that activate NRF2, we determined whether these agents would sensitize NQO1-low melanoma cells to 17-AAG. Synergistic cytotoxicity of the 17-AAG and CDDP combination was detected in four out of five NQO1-low cell lines, but not in the cell line with KEAP1 mutation. These data indicate that 17-AAG could be a potential chemotherapeutic agent for melanoma with KEAP1 mutation or NQO1 expression.

2016-01-01 | S-EPMC4821458 | BioStudies

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