Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance
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PRECLINICAL STUDIES
Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance Hao Chen 1 & Xiaoling Zhu 1 & Rong Sun 2 & Panpan Ma 2 & Erhao Zhang 2 & Zhou Wang 3 & Yihui Fan 2,4 & Guoxiong Zhou 1 & Renfang Mao 2,5 Received: 1 December 2019 / Accepted: 10 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary 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. Ubiquitinspecific 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. Keywords Pancreatic ductal adenocarcinoma . USP7 . chemoresistance . translation
Introduction Pancreatic ductal adenocarcinoma (PDAC) is an exocrine cancer that develops from pancreatic ductal epithelial cells.
* Guoxiong Zhou [email protected] * Renfang Mao [email protected] 1
Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Jiangsu, Nantong, China
2
Laboratory of Medical Science, School of Medicine, Nantong University, 226001 Jiangsu, China
3
School of Life Sciences, Nantong University, 226001 Jiangsu, China
4
Department of Immunology, School of Medicine, Nantong University, 226001 Jiangsu, China
5
Department of Pathophysiology, School of Medicine, Nantong University, 19 Qixiu Road, 226001 Jiangsu, Nantong, People’s Republic of China
Worldwide, there are an estimated 12.9 per 100,000 new cases per year and 11.0 per 100,000 deaths per year. PDAC is one of the most malignant cancers. Only about 6% of patients survive 5 years after diagnosis and most patients die within one year of diagnosis. This high mortality rate is because of the limite
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