Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice, Nude
Pancreatic Neoplasms
/ drug therapy
Thiophenes
/ pharmacology
Ubiquitin-Specific Peptidase 7
/ antagonists & inhibitors
Pancreatic ductal adenocarcinoma
USP7
chemoresistance
translation
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
01
12
2019
accepted:
10
05
2020
pubmed:
30
5
2020
medline:
11
9
2021
entrez:
30
5
2020
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and most patients die within one year after diagnosis. This cancer is resistant to almost all current therapies, so there is an urgent need to identify novel druggable targets. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that functions in carcinogenesis, but its role in PDAC is unknown. Our experiments indicated that several subtypes of PDAC cells are sensitive to USP7 inhibition. In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell death in vitro and in vivo. Pharmaceutical inhibition of USP7 in P22077-resistant PDAC cells allowed them to overcome chemoresistance. Genetic silencing experiments supported the importance of USP7 in the pathogenesis of PDAC. In particular, genetic disruption of USP7 greatly reduced cell proliferation and chemoresistance in vitro and prevented PDAC growth in vivo. Protein profiling by mass spectrometry (MS) indicated USP7 was associated 4 ontology terms: translation, localization and protein transporting, nucleotide or ribonucleotide binding, and ubiquitin-dependent catabolic processes. Puromycin labeling indicated that P22077 greatly reduced protein synthesis, and transcriptional analysis indicated that P22077 significantly altered the extracellular space matrix. In summary, we provided multiple lines of evidence which indicate that USP7 plays a critical role in PDAC, and may therefore be a suitable target for treatment of this cancer.
Identifiants
pubmed: 32468271
doi: 10.1007/s10637-020-00951-0
pii: 10.1007/s10637-020-00951-0
doi:
Substances chimiques
1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
0
Antineoplastic Agents
0
Thiophenes
0
Ubiquitin-Specific Peptidase 7
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1707-1716Références
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