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Series GSE186447 Query DataSets for GSE186447
Status Public on Sep 08, 2022
Title NCP26 is a potent prolyl-tRNA synthetase inhibitor and induces pro- apoptotic responses with in vivo potency in multiple myeloma. Single-cell RNA-seq data BM samples.
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Glutamyl-prolyl-tRNA synthetase (EPRS) is a unique bifunctional aminoacyl-tRNA synthetase which catalyzes the ATP-dependent aminoacylation of glutamyl and prolyl residues to cognate tRNAs, constituting fundamental building blocks in protein synthesis. Genomic data suggest that EPRS promotes disease progression and is associated with poor prognosis in multiple myeloma (MM), while downregulation of EPRS triggers MM cell apoptosis implying an amino acid starvation response as a central mechanism. We developed a novel ATP competitive inhibitor, NCP26, targeting the prolyl-tRNA synthetase (PRS) component. The inhibitor demonstrates significant anti-tumor activity against human MM cell lines, regardless of their sensitivity to other therapeutic agents, against patient MM cells and is active in vivo using a MM xenograft mouse model. In contrast to the proline competitive PRS inhibitor halofuginone, NCP26 effects are not altered by exogenous proline levels. NCP26 treatment induces G0/G1 cell cycle arrest followed by apoptotic MM cell death, evidenced by depletion of mitochondrial membrane potential as well as caspase and PARP cleavage. Using combined transcriptomic and proteomic approaches we demonstrate a complex phenotypic response involving multiple pathways in protein quality control which center around the ribosome as integrating hub. Furthermore, we identified multiple proline rich motif containing protein targets of NCP26 as downstream effectors. These include myeloma survival factors such as syndecan 1 (SDC1, CD138), or basic helix-loop-helix transcription factors such as MYC, and transcription factor 3 (TCF3) suggesting that acute blockade of prolyl- aminoacylation evokes a complex pro-apoptotic response beyond the canonical amino acid starvation and integrated stress response. Taken together, our pre-clinical studies validate EPRS as a possible therapeutic target and provide the framework for evaluation of PRS inhibitors in a clinical setting.
 
Overall design 3 separate experiments. Experiment 1 = 1 patient, 7 treatment samples. Experiment 2 = 1 patient, 11 treatment samples. Experiment 3= 2 patients, 16 different treatment samples = 32 samples
 
Contributor(s) James-Bott A, Cribbs A
Citation(s) 36631435
Submission date Oct 22, 2021
Last update date Jan 25, 2023
Contact name Adam Cribbs
Organization name University of Oxford
Department NDORMS
Lab The Oppermann Group
Street address Botnar Research Centre
City Oxford
State/province Oxfordshire
ZIP/Postal code OX3 7LD
Country United Kingdom
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (26)
GSM5652032 ORB8266-Casin
GSM5652033 ORB8266-DMSO
GSM5652034 ORB8266-GSKJ4
This SubSeries is part of SuperSeries:
GSE186448 NCP26 is a potent prolyl-tRNA synthetase inhibitor and induces pro- apoptotic responses with in vivo potency in multiple myeloma
Relations
BioProject PRJNA773807
SRA SRP342755

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE186447_RAW.tar 1.5 Gb (http)(custom) TAR (of MTX, TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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