PXD023260

PXD023260 is an original dataset announced via ProteomeXchange.

Title	Nelfinavir overcomes proteasome inhibitor resistance in multiple myeloma by modulating lipid bilayer composition and fluidity
Description	Nelfinavir has broad anti-cancer activity precilincally as a single agent and in combination. Clinically, it is particularly effective in the therapy of proteasome inhibitor-refractory multiple myeloma. The broad anti-cancer mechanism of action of nelfinavir implies that it may interfere with very fundamental aspects of cancer cell biology. We combined proteome-wide affinity-purification with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir alongside with candidate genetic contributors affecting nelfinavir cytotoxicity. We show that nelfinavir has multiple binding partners embedded in organellar lipid-rich membranes. By binding to these, nelfinavir affects the composition and fluidity of lipid-rich membranes, which subsequently disrupts downstream membrane-related processes, such as lipid metabolism, glucose processing, mitochondrial respiration, vesicular transport and ABCB1-mediated drug efflux. Targeting membrane fluidity by FDA-approved drug nelfinavir is a potent mechanism to achieve anti-cancer activity and is in particular suitable for the treatment of proteasome inhibitor-refractory multiple myeloma.
HostingRepository	PRIDE
AnnounceDate	2021-11-02
AnnouncementXML	Submission_2021-11-02_04:27:19.338.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bogdan Florea
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-21 11:49:15	ID requested
⏵ 1	2021-11-02 04:27:20	announced

Besse L, Besse A, Stolze SC, Sobh A, Zaal EA, van der Ham AJ, Ruiz M, Phuyal S, B, ü, chler L, Sathianathan M, Florea BI, Bor, é, n J, St, å, hlman M, Huber J, Bolomsky A, Ludwig H, Hannich JT, Loguinov A, Everts B, Berkers CR, Pilon M, Farhan H, Vulpe CD, Overkleeft HS, Driessen C, Treatment with HIV-Protease Inhibitor Nelfinavir Identifies Membrane Lipid Composition and Fluidity as a Therapeutic Target in Advanced Multiple Myeloma. Cancer Res, 81(17):4581-4593(2021) [pubmed]

submitter keyword: HIV-protease inhibitor, nelfinavir, multiple myeloma, affinity-purification, CRISPR/Cas9, ADIPOR2, UPR, proteasome inhibitors, ezetimibe

Lenka Besse
contact affiliation	Lenka Besse, PhD Department of Oncology and Hematology, Kantonsspital St Gallen, Rorschacherstrasse 95, St Gallen, Switzerland e-mail: lenka.kubiczek@gmail.com / Lenka.besse@kssg.ch phone: +41 (0) 71 494 1162
contact email	Lenka.besse@kssg.ch
lab head
Bogdan Florea
contact affiliation	Leiden Institute for Chemistry
contact email	b.florea@chem.leidenuniv.nl
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/2021/11/PXD023260

PRIDE project URI

• PRIDE
  1. PXD023260
     1. Label: PRIDE project
     2. Name: Nelfinavir overcomes proteasome inhibitor resistance in multiple myeloma by modulating lipid bilayer composition and fluidity