PXD060338-1

PXD060338 is an original dataset announced via ProteomeXchange.

Title	Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer
Description	Cholesterol (CHOL) homeostasis is significantly modulated in prostate cancer (PCa) suggesting an active role in PCa development and progression. Several studies indicate a strong correlation between elevated CHOL levels and increased PCa risk and severity. Inhibition of CHOL biosynthesis at different steps including lanosterol synthase (LSS) has shown significant efficacy against both hormone-dependent and castration-resistant PCa. Earlier, we reported proteasomal degradation of AR/AR-Vs and Mnk1/2 as the primary mechanisms of action of VNPP433-3β in inhibiting PCa cell proliferation and tumor growth. Through thermal proteome profiling, comparative proteomics and cellular thermal shift assay, we identified VNPP433-3β's ancillary effect of lowering CHOL by binding to LSS and lanosterol 14-alpha demethylase, potentially inhibiting CHOL biosynthesis in PCa cells and tumors. Additionally, in conjunction with our previously reported transcriptome analysis, proteomics reveals that VNPP433-3β modulated upstream regulators and pathways critical for PCa stem cell maintenance and recurrence. The inhibition of CHOL biosynthesis by VNPP433-3β reinforces its multifaceted effects in PCa across all stages, highlighting its potential as a single-agent therapy. Achieving reduced CHOL levels aligns with better treatment outcomes, further substantiating VNPP433-3β’s therapeutic potential.
HostingRepository	PRIDE
AnnounceDate	2025-08-25
AnnouncementXML	Submission_2025-08-25_11:52:54.121.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mehari Weldemariam
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-29 14:01:08	ID requested
⏵ 1	2025-08-25 11:52:55	announced

Thankan RS, Thomas E, Weldemariam MM, Purushottamachar P, Huang W, Kane MA, Zhang Y, Ambulos N, Wang BD, Weber D, Njar VCO, in castration-resistant prostate cancer. Mol Oncol, 19(8):2292-2309(2025) [pubmed]

10.1002/1878-0261.70009;

submitter keyword: Next generation galeterone analog, CYP51A1, thermal proteome profiling, cholesterol, prostate cancer, lanosterol synthase

Maureen A. Kane
contact affiliation	Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
contact email	mkane@rx.umaryland.edu
lab head
Mehari Weldemariam
contact affiliation	University of Maryland Baltimore
contact email	mweldemariam@rx.umaryland.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060338
     1. Label: PRIDE project
     2. Name: Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer