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Circumvention and reactivation of the p53 oncogene checkpoint in mouse colon tumors

Wataru Aizu1, Glenn S Belinsky, Christopher Flynn

  • 1Department of Molecular & Cell Biology, 91 North Eagleville Road, University of Connecticut, Storrs, CT 06269-3125, USA.

Biochemical Pharmacology
|September 5, 2006
PubMed

Insights

Mdm2 inhibitors like Nutlin-3 effectively activate the p53 tumor suppressor in mouse colon cancer models with wild-type p53. This targeted approach shows promise for treating colon cancers while sparing normal tissue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Azoxymethane (AOM)-induced mouse colon tumors with sequence-normal p53 are valuable models for human colon cancer.
  • Constitutively expressed Mdm2 negatively regulates p53 in these tumor cells, despite p19/ARF expression.
  • The Mdm2 inhibitory protein p19/ARF is expressed but insufficient for p53 activation in AJ02-NM(0) cells.

Purpose of the Study:

  • To evaluate the efficacy of the Mdm2 inhibitor Nutlin-3 in AOM-induced mouse colon tumors.
  • To compare Nutlin-3's effects on p53 activation and downstream targets with conventional chemotherapeutics.
  • To assess the potential of Mdm2 inhibitors for selective targeting of colon cancers with wild-type p53.

Main Methods:

  • Utilized a cell line (AJ02-NM(0)) derived from AOM-induced colon tumors for in vitro studies.
  • Performed cellular localization and co-immunoprecipitation experiments to identify p53 regulators.
  • Administered Nutlin-3 to cells and tumor tissues, assessing p53 DNA binding, target gene expression (Bax, PERP), cell cycle arrest, and apoptosis.
  • Compared responses to doxorubicin and 5-fluorouracil (5-FU).

Main Results:

  • Nutlin-3 activated p53 DNA binding in AJ02-NM(0) cells, comparable to doxorubicin and 5-FU.
  • Nutlin-3 significantly upregulated p53 target genes Bax and PERP, exceeding the effects of doxorubicin or 5-FU.
  • Nutlin-3 induced a G2/M phase cell cycle arrest, distinct from the G1 arrest caused by doxorubicin and 5-FU.
  • Ex vivo studies showed Nutlin-3 activated p53 target gene expression and apoptosis in AOM-induced tumor tissue but not in normal mucosa.

Conclusions:

  • Mdm2 inhibitors, exemplified by Nutlin-3, demonstrate selective efficacy against colon cancers retaining a wild-type p53 gene.
  • The AOM-induced mouse colon tumor model is suitable for preclinical evaluation of Mdm2 inhibitors.
  • Nutlin-3 offers a promising therapeutic strategy for targeting specific colon cancer subtypes while minimizing toxicity to normal tissues.

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