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Proteomics identifi...
Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
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- Fotouhi, Omid (author)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Kjellin, Hanna (author)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden
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- Juhlin, C. Christofer (author)
- Karolinska Institutet,Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden
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- Pan, Yanbo (author)
- Karolinska Institutet,Karolinska Inst, Sweden; SciLifeLab, Sweden
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- Vesterlund, Mattias (author)
- Karolinska Institutet,Karolinska Inst, Sweden; SciLifeLab, Sweden
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- Ghaderi, Mehran (author)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Yousef, Abdelhamid (author)
- Univ Cambridge, Dept Pharmacol, Cambridge, England
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- Andersson-Sand, Hillevi (author)
- Karolinska Institutet,SciLifeLab, Sweden
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- Kharaziha, Pedram (author)
- Karolinska Institutet,Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Region Östergötland, Klinisk genetik,Linkoping Univ Hosp, Dept Clin Genet, Linkoping, Sweden
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- Caramuta, Stefano (author)
- Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Uppsala Univ, Sweden
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- Kjellman, Magnus (author)
- Karolinska Institutet,Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden
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- Zedenius, Jan (author)
- Karolinska Institutet,Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden
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- Larsson, Catharina (author)
- Karolinska Institutet,Karolinska Inst, Sweden
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- Orre, Lukas M. (author)
- Karolinska Institutet,Karolinska Inst, Sweden; SciLifeLab, Sweden
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(creator_code:org_t)
- 2019-08-12
- 2019
- English.
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In: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- art (subject category)
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Oncogene
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- By the author/editor
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Fotouhi, Omid
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Kjellin, Hanna
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Juhlin, C. Chris ...
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Pan, Yanbo
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Vesterlund, Matt ...
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Ghaderi, Mehran
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Yousef, Abdelham ...
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Andersson-Sand, ...
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Kharaziha, Pedra ...
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Caramuta, Stefan ...
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Kjellman, Magnus
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Zedenius, Jan
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Larsson, Cathari ...
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Orre, Lukas M.
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- MEDICAL AND HEALTH SCIENCES
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Oncogene
- By the university
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Linköping University
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Uppsala University
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Karolinska Institutet