PXD018387 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma |
Description | Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating this resistance, we mapped genetic co-dependencies associated with the proteasome. These studies identified cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, mirroring recent studies that have shown mechanism of overcoming PI-induced stress. Here, we first underscore this relationship by mapping genetic co-dependencies in cancer proteostasis. These results lead us to explore HSP70 inhibitors as potential 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 response to PI. 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. This dataset corresponds to figure 5, experiment outlined in figure 5a. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_05:02:31.968.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Ian Ferguson |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monohydroxylated residue; acetylated residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-04-06 01:22:00 | ID requested | |
1 | 2020-04-24 02:12:11 | announced | |
⏵ 2 | 2024-10-22 05:02:32 | announced | 2024-10-22: Updated project metadata. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: TMT, HSP70, pulsed-silac,Multiple Myeloma |
Contact List
Arun Wiita |
contact affiliation | Department of Laboratory Medicine, Wiita Lab, University of California, San Francisco, USA |
contact email | arun.wiita@ucsf.edu |
lab head | |
Ian Ferguson |
contact affiliation | Stanford University |
contact email | ifergus@stanford.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD018387
- Label: PRIDE project
- Name: Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma