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- Title
Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors.
- Authors
Briest, Franziska; Grass, Irina; Sedding, Dagmar; Möbs, Markus; Christen, Friederike; Benecke, Joana; Fuchs, Karolin; Mende, Stefanie; Kaemmerer, Daniel; Sänger, Jörg; Kunze, almut; Geisler, Christina; Freitag, Helma; Lewens, Florentine; Worpenberg, Lina; Iwaszkiewicz, Sara; Siegmund, Britta; Walther, Wolfgang; Hummel, Michael; Grabowski, Patricia
- Abstract
<bold><italic>Background/Aims:</italic></bold> The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo<italic>.</italic><bold><italic>Methods:</italic></bold> By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. <bold><italic>Results:</italic></bold> The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. <bold><italic>Conclusion:</italic></bold> In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors.
- Subjects
NEUROENDOCRINE tumors; TUMOR suppressor proteins; UBIQUITIN ligases; FORKHEAD transcription factors; GENE expression; CELLULAR signal transduction; GENETICS
- Publication
Neuroendocrinology, 2018, Vol 107, Issue 1, p1
- ISSN
0028-3835
- Publication type
Article
- DOI
10.1159/000481506