Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
| Autor: | Omid Fotouhi, Magnus Kjellman, Catharina Larsson, Mehran Ghaderi, Mattias Vesterlund, Stefano Caramuta, Jan Zedenius, Lukas M. Orre, C. Christofer Juhlin, Yanbo Pan, Abdelhamid Yousef, Hanna Kjellin, Hillevi Andersson-Sand, Pedram Kharaziha |
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| Přispěvatelé: | Juhlin, C Christofer [0000-0002-5945-9081], Vesterlund, Mattias [0000-0001-9471-6592], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Proteomics Cancer Research NEDD8 Protein Cell- och molekylärbiologi Apoptosis Cyclopentanes Biology NEDD8 03 medical and health sciences 0302 clinical medicine Ubiquitin Cell Line Tumor Proliferating Cell Nuclear Antigen Intestinal Neoplasms Intestine Small Genetics medicine Gene silencing Humans RNA Small Interfering Molecular Biology Ubiquitins Aged Cancer och onkologi Bortezomib Middle Aged Neuroendocrine Tumors 030104 developmental biology Pevonedistat Pyrimidines Proteasome 030220 oncology & carcinogenesis Cancer and Oncology Cancer research Proteasome inhibitor biology.protein Female Neddylation Carrier Proteins Cell and Molecular Biology medicine.drug |
| Popis: | Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET. Funding Agencies|NovartisNovartis; Swedish Research CouncilSwedish Research Council; Swedish Cancer SocietySwedish Cancer Society; Cancer Society in Stockholm; Gustav V Jubilee Foundation; Stockholm County CouncilStockholm County Council; Karolinska InstitutetKarolinska Institutet |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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