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Oncogene. 2019 Aug 12. doi: 10.1038/s41388-019-0938-8. [Epub ahead of print]

Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.

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Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Department of Pathology and Cytology, Karolinska University Hospital Solna, Stockholm, Sweden.
SciLifeLab, Stockholm, Sweden.
Department of Pharmacology, Cambridge University, Cambridge, UK.
Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital Solna, Stockholm, Sweden.
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
SciLifeLab, Stockholm, Sweden.


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.


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