TY  - JOUR
A1  - Briest, Franziska
A1  - Grass, Irina
A1  - Sedding, Dagmar
A1  - Moebs, Markus
A1  - Christen, Friederike
A1  - Benecke, Joana
A1  - Fuchs, Karolin
A1  - Mende, Stefanie
A1  - Kaemmerer, Daniel
A1  - Sänger, Jörg
A1  - Kunze, Almut
A1  - Geisler, Christina
A1  - Freitag, Helma
A1  - Lewens, Florentine
A1  - Worpenberg, Lina
A1  - Iwaszkiewicz, Sara
A1  - Siegmund, Britta
A1  - Walther, Wolfgang
A1  - Hummel, Michael
A1  - Grabowski, Patricia
T1  - Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors
JF  - Neuroendocrinology : international journal for basic and clinical studies on neuroendocrine relationships
N2  - Background/Aims: 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. 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, 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. 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 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. 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. (c) 2017 S. Karger AG, Basel
KW  - Neuroendocrine tumors
KW  - Signaling
KW  - MDM2
KW  - p53
KW  - FOXM1
KW  - Targeted therapy
Y1  - 2017
U6  - https://doi.org/10.1159/000481506
SN  - 0028-3835
SN  - 1423-0194
VL  - 107
IS  - 1
SP  - 1
EP  - 23
PB  - Karger
CY  - Basel
ER  -