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Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: therapeutic application in multiple myeloma

ABSTRACT: Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: therapeutic application in multiple myeloma

PROVIDER: PRJNA1005973 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25656561_1.fastq.gz	Fastqsanger.gz
	SRR25656561_2.fastq.gz	Fastqsanger.gz
	SRR25656562_1.fastq.gz	Fastqsanger.gz
	SRR25656562_2.fastq.gz	Fastqsanger.gz
	SRR25656563_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: therapeutic application in multiple myeloma

Project description:Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and delayed the survival of MM tumour-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signalling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signalling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

2023-08-18 | GSE240978 | GEO

Ubiquitin proteasome expression in Mulitple Myeloma cell lines

Project description:The ubiquitin proteasome system plays an important role in the pathophysiology of Multiple Myeloma, highlighted by the unique success of proteasome inhibitors in this malignancy. Using topic-defined microarrays we have looked at expression of ubiquitin proteasome system genes in 2 multiple myeloma cell lines and normal bone marrow samples.

2016-10-31 | GSE78884 | GEO

Secondary proteasome inhibitor carfilzomib resistant myeloma cell lines

Project description:Modulation of the activity of the ubiquitin-proteasome pathway with the proteasome inhibitor (PI) is an established component of therapy for plasma cell disorders. However, resistance emerges and the mechanism is incompletely understood. We generated carfilzomib-resistant (CR) myeloma cell lines by exposing drug-naive ANBL-6, KAS-6/1, U266, and OPM-2 cells to increasing concentrations of carfilzomib and then performed gene expression profiling (GEP) to identify prominent changes compared to their vehicle-treated counterparts, followed by exploration of the mechanism(s) of proteasome inhibitor resistance.

2016-10-09 | GSE62237 | GEO

The mitochondrial protease LonP1 promotes proteasome inhibitor resistance in multiple myeloma.

Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin or clinically-approved proteasome inhibitor bortezomib and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.

2021-03-06 | GSE166122 | GEO

Tight Junction Protein 1 is a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma

Project description:Proteasome inhibitors are important chemotherapeutics in the treatment of multiple myeloma, but they are currently used empirically as no markers of sensitivity have been validated. We have identified expression of tight junction protein (TJP) 1 as being associated with sensitivity of plasma cells in vitro and in vivo to proteasome inhibitors. TJP1 suppressed expression of genes in the major histocompatibility class II region, including two catalytically active immunoproteasome subunits, thereby decreasing proteasome activity, a critical determinant of proteasome inhibitor sensitivity. This occurred through suppression by TJP1 of signaling through the epidermal growth factor receptor/Janus kinase 1/signal transducer and activator of transcription 3 pathway. In the clinic, high TJP1 expression in myeloma patients was associated with a significantly higher likelihood of responding to bortezomib, and with a longer time-to-progression after treatment. Taken together, these data support the use of TJP1 as a biomarker of sensitivity and resistance to proteasome inhibitors. To further elucidate mechanisms of bortezomib resistance, we developed human-derived multiple myeloma cell lines with a 4-fold or greater resistance to bortezomib. Then total RNA for bortezomib resistant (BR) and wild type (WT) was extracted and used for comparison by gene expression profiling.

2015-12-31 | E-GEOD-52369 | biostudies-arrayexpress

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first map proteasome-associated genetic co-dependencies. We identify cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors as myeloma therapeutics. We show these compounds exhibit increased efficacy against both acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC proteomics reveal that JG’s overcome PI resistance not via the expected mechanism of inhibiting cytosolic HSP70s, but instead through mitochondrial-localized HSP70, HSPA9, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize dynamics of myeloma proteostasis networks under therapeutic pressure while further motivating investigation of HSPA9 as a specific target in PI-resistant disease.

2020-04-15 | GSE148659 | GEO

Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

2022-05-27 | PXD032030 | Pride

Tight Junction Protein 1 is a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma

2015-12-31 | GSE52369 | GEO

Proteasome inhibition silences oncogenic transcripts in multiple myeloma through HDAC3-mediated DNA condensation and gene relocation [CUT&RUN]

Project description:This study provides a genome-wide map of changes in degradative ubiquitination in response to proteasome inhibition in the multiple myeloma cell line MM.1S. Following proteasome inhibition with lactacystin, CUT and RUN assays were carried out to determine the genomic locations of ubiquitin in multiple myeloma cells stably expressing a flagged version of ubiquitin (MM.1S-3XFlag Ubiquitin cells). In addition, we report the DNA binding locations of the transcription factor c-MYC in basal conditions in MM.1S parental cells.

2022-11-21 | GSE193302 | GEO

Proteasome inhibition silences oncogenic transcripts in multiple myeloma through HDAC3-mediated DNA condensation and gene relocation [RNA-seq]

Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.

2022-11-21 | GSE193300 | GEO

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