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Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Pathol & Cytol, Stockholm, Sweden.
Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;SciLifeLab, Stockholm, Sweden.
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2019 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 43, p. 6881-6897Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 38, no 43, p. 6881-6897
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-396952DOI: 10.1038/s41388-019-0938-8ISI: 000492728000001PubMedID: 31406256OAI: oai:DiVA.org:uu-396952DiVA, id: diva2:1370583
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Cancer Society in StockholmStockholm County CouncilKing Gustaf V Jubilee FundAvailable from: 2019-11-15 Created: 2019-11-15 Last updated: 2019-11-15Bibliographically approved

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