PXD054626

PXD054626 is an original dataset announced via ProteomeXchange.

Title	Apoptotic priming in senescence predicts selective senolysis by quantitative analysis of mitochondrial dependencies
Description	Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.
HostingRepository	PRIDE
AnnounceDate	2024-12-17
AnnouncementXML	Submission_2024-12-17_10:11:34.176.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gary Bradshaw
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-06 01:30:21	ID requested
⏵ 1	2024-12-17 10:11:34	announced

Dataset with its publication pending

submitter keyword: Cellular senescence, Navitoclax (ABT263)

Anthony Letai
contact affiliation	Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
contact email	anthony_letai@dfci.harvard.edu
lab head
Gary Bradshaw
contact affiliation	Harvard Medical School
contact email	bradshga@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054626
     1. Label: PRIDE project
     2. Name: Apoptotic priming in senescence predicts selective senolysis by quantitative analysis of mitochondrial dependencies