{"entity": "publication", "iuid": "0982a4fafbd9457fa5129dfa54859ac3", "timestamp": "2026-08-20T20:57:08.908Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0982a4fafbd9457fa5129dfa54859ac3.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0982a4fafbd9457fa5129dfa54859ac3"}}, "title": "Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.", "authors": [{"family": "Fotouhi", "given": "Omid", "initials": "O"}, {"family": "Kjellin", "given": "Hanna", "initials": "H"}, {"family": "Juhlin", "given": "C Christofer", "initials": "CC", "orcid": "0000-0002-5945-9081", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c155b3a3146b41909170a016a7f5b07a.json"}}, {"family": "Pan", "given": "Yanbo", "initials": "Y"}, {"family": "Vesterlund", "given": "Mattias", "initials": "M", "orcid": "0000-0001-9471-6592", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e443cdb01cc44a7fa786941b5c0b62d6.json"}}, {"family": "Ghaderi", "given": "Mehran", "initials": "M"}, {"family": "Yousef", "given": "Abdelhamid", "initials": "A"}, {"family": "Andersson-Sand", "given": "Hillevi", "initials": "H"}, {"family": "Kharaziha", "given": "Pedram", "initials": "P"}, {"family": "Caramuta", "given": "Stefano", "initials": "S"}, {"family": "Kjellman", "given": "Magnus", "initials": "M"}, {"family": "Zedenius", "given": "Jan", "initials": "J"}, {"family": "Larsson", "given": "Catharina", "initials": "C"}, {"family": "Orre", "given": "Lukas M", "initials": "LM"}], "type": "journal article", "published": "2019-10-00", "journal": {"title": "Oncogene", "issn": "1476-5594", "volume": "38", "issue": "43", "pages": "6881-6897", "issn-l": "0950-9232"}, "abstract": "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.", "doi": "10.1038/s41388-019-0938-8", "pmid": "31406256", "labels": [], "xrefs": [{"db": "pii", "key": "10.1038/s41388-019-0938-8"}], "notes": [], "created": "2026-08-20T08:48:19.511Z", "modified": "2026-08-20T08:48:19.644Z"}