PXD041167-1

PXD041167 is an original dataset announced via ProteomeXchange.

Title	Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute contractility impairment due to dysbalance of calcium homeostasis
Description	Treatment of multiple myeloma (MM) with the second-generation proteasome inhibitor (PI) carfilzomib (CFZ) is associated with higher incidence of cardiovascular adverse events compared to first-generation PI bortezomib (BTZ). CFZ and BTZ inhibit at lower doses only the β5 proteasome subunit, whereas they differ in co-inhibition of other proteasome subunits at the higher doses: BTZ co-inhibits β1 subunit, whereas CFZ co- inhibits β2 subunit. This different pattern of inhibition affects differently the degree of functional proteasome inhibition with β5+β2 showing more effective functional proteasome inhibition. It is unclear, whether CFZ-induced cardiotoxicity is the result of proteasome inhibition, or an off-target effect. With an unbiased multi-omics approach in conjunction with proteasome subunit-specific inhibitors, we show that CFZ-type β5+β2 proteasome subunit inhibition, in contrast to the BTZ-type β5+β1 inhibition, directly interferes with cardiomyocyte contractility in vitro and in vivo. For the in vivo analysis, we used 6-8 weeks old Balb/c mice that were exposed to the drugs for 1h and subsequently euthanized. The hearts were processed for LC/MS-MS analysis. The hearts from CFZ-treated mice for 1h show showed impaired accumulation of proteins related to calcium handling (Atp2a2) and retinoid pathway (Aldh1a1), which is prevented by atRA (1 mg/kg) co-treatment. Our data suggests a novel mechanism for PI-induced cardiotoxicity that reflects clinical findings in which CFZ-type β5+β2 proteasome inhibition, in contrast to β5+β1 co-inhibition of BTZ, directly interferes with the contractile activity of cardiomyocytes.
HostingRepository	PRIDE
AnnounceDate	2025-08-12
AnnouncementXML	Submission_2025-08-12_09:53:27.588.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lenka Besse
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-28 06:48:43	ID requested
⏵ 1	2025-08-12 09:53:27	announced

10.1016/J.ISCI.2025.113228;

submitter keyword: mouse, heart, atRA, carfilzomib, proteasome

Lenka Besse
contact affiliation	Cantonal Hospital St. Gallen, Switzerland
contact email	lenka.besse@kssg.ch
lab head
Lenka Besse
contact affiliation	Cantonal Hospital St. Gallen
contact email	lenka.besse@kssg.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041167
     1. Label: PRIDE project
     2. Name: Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute contractility impairment due to dysbalance of calcium homeostasis