Mechanisms of targeting the MDM2-p53-FOXM1 axis in well-differentiated intestinal neuroendocrine tumors

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Item Type:	Article
Title:	Mechanisms of targeting the MDM2-p53-FOXM1 axis in well-differentiated intestinal neuroendocrine tumors
Creators Name:	Briest, F., Grass, I., Sedding, D., Moebs, M., Christen, F., Benecke, J., Fuchs, K., Mende, S., Kaemmerer, D., Saenger, J., Kunze, A., Geisler, C., Freitag, H., Lewens, F., Worpenberg, L., Iwaszkiewicz, S., Siegmund, B., Walther, W., Hummel, M. and Grabowski, P.
Abstract:	BACKGROUND/AIMS: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of p53 negative regulators, 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. METHODS: 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, immune fluorescence, western blot and multiplex gene expression analysis. Finally, we analyzed the anti-tumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. RESULTS: 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 re-activated an anti-proliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decrease 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 anti-proliferative effects. CONCLUSION: 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.
Keywords:	Neuroendocrine Tumors, Signaling, MDM2, p53, FOXM1, Targeted Therapy, Animals, Mice
Source:	Neuroendocrinology
ISSN:	0028-3835
Publisher:	Karger
Volume:	107
Number:	1
Page Range:	1-23
Date:	July 2018
Official Publication:	https://doi.org/10.1159/000481506
PubMed:	View item in PubMed

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