In:
Neuroendocrinology, S. Karger AG, Vol. 107, No. 1 ( 2018), p. 1-23
Abstract:
〈 b 〉 〈 i 〉 Background/Aims: 〈 /i 〉 〈 /b 〉 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 〈 i 〉 . 〈 /i 〉 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 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.
Type of Medium:
Online Resource
ISSN:
0028-3835
,
1423-0194
Language:
English
Publisher:
S. Karger AG
Publication Date:
2018
detail.hit.zdb_id:
1483028-0
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