PXD024742

PXD024742 is an original dataset announced via ProteomeXchange.

Title	The M1 aminopeptidase NPEPPS is a novel regulator of cisplatin sensitivity
Description	Platinum-based chemotherapeutics are used in many combination regimens in cancer. Despite extensive use across diverse cancer types, there is room for improved efficacy and patient selection for treatment. Here, we use bladder cancer to address both issues. A multi-omic assessment of five human bladder cancer cell lines and their chemotherapy resistant derivatives, coupled with in vitro whole-genome CRISPR screens were used to define functional drivers of treatment resistance. We identified 46 genes that sensitized the resistant cell lines to cisplatin plus gemcitabine (GemCis), a standard combination therapy in bladder cancer. Most genes were involved with DNA damage and repair pathways, which have previously been associated with enhanced sensitivity to cisplatin. Evaluating expression of the 46 genes in the whole transcriptome and proteome data in parental and resistant lines identified the puromycin sensitive aminopeptidase, NPEPPS, as a novel hit. Depletion of NPEPPS resulted in sensitizing resistant bladder cancer cells to cisplatin in vitro and in xenograft experiments. Pharmacologic inhibition of NPEPPS with tosedostat in cells and in chemoresistant, bladder cancer patient-derived tumoroids improved response to cisplatin. Prior work found NPEPPS in a protein complex with volume regulated anion channels (VRACs) in several cell line models. Interestingly, depletion of two VRAC subunits, LRRC8A and LRRC8D, known importers of intracellular cisplatin, enhanced resistance to cisplatin. Our findings support NPEPPS as a novel and druggable driver of cisplatin resistance with the potential for rapid translation to clinical investigation.
HostingRepository	PRIDE
AnnounceDate	2024-02-20
AnnouncementXML	Submission_2024-02-20_14:50:04.131.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sarah Parker
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-15 06:27:56	ID requested
⏵ 1	2024-02-20 14:50:04	announced

Dataset with its publication pending

submitter keyword: DNA Repair, LRRC8A, LRRC8D, Tosedostat, Volume Regulated Anion Channel, Synthetic Lethality, Transcriptomics,Bladder Cancer, Genomics, Chemotherapy, VRAC, CRISPR Screen, NPEPPS, Proteomics, Cisplatin

James C. Costello
contact affiliation	Department of Pharmacology University of Colorado Anschutz Medical Campus
contact email	JAMES.COSTELLO@CUANSCHUTZ.EDU
lab head
Sarah Parker
contact affiliation	Cedars-Sinai Medical Center
contact email	sarah.parker@cshs.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/02/PXD024742

PRIDE project URI

• PRIDE
  1. PXD024742
     1. Label: PRIDE project
     2. Name: The M1 aminopeptidase NPEPPS is a novel regulator of cisplatin sensitivity