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Original Paper

Advanced Release (accepted, unedited manuscript)

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

Briest F · Grass I · Sedding D. · Möbs M. · Christen F · Benecke J. · Fuchs K. · Mende S. · Kaemmerer D. · Sänger J. · Kunze A. · Geisler C. · Freitag H · Lewens F · Worpenberg L. · Iwaszkiewicz S · Siegmund B · Walther W. · Hummel M. · Grabowski P

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Article / Publication Details

Received: March 23, 2017
Accepted: September 13, 2017
Published online: September 14, 2017

Number of Print Pages: 23
Number of Figures: 12
Number of Tables: 1

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN

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.

©2017S. Karger AG, Basel


Article / Publication Details

Received: March 23, 2017
Accepted: September 13, 2017
Published online: September 14, 2017

Number of Print Pages: 23
Number of Figures: 12
Number of Tables: 1

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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