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

Authors

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

Journal

  • Neuroendocrinology

Citation

  • Neuroendocrinology 107 (1): 1-23

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.


DOI

doi:10.1159/000481506