Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

Gene Ther. 2001 Sep;8(18):1401-8. doi: 10.1038/sj.gt.3301538.

Abstract

p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro) are resistant to p53. To explore the potential use of two p53 homologues, p73 and p51/p63, in cancer gene therapy, we introduced p53, p73 and p51/p63 into colorectal cancer cell lines via adenoviral vectors, and compared their effects on cell growth. Among 10 cell lines tested, six cell lines displayed a similar response following transduction of p53, p73beta or p51A/p63gamma; two lines underwent cell-cycle arrest, three lines exhibited apoptosis and one line showed no-effect following transduction. The effect on cell-cycle progression was variable in the other four cell lines. Interestingly, three cell lines were resistant to p53-mediated apoptosis, including two lines having endogenous wild-type p53 alleles, but underwent apoptosis after transduction of p73beta or p51A/p63gamma. Similar to p53, transduction of p51A/p63gamma induced extensive apoptosis when combined with adriamycin or X-radiation in SW480 cells, which are normally resistant to apoptosis. Transduction of p73beta and p51A/p63gamma also reduced the tumorigenicity of two colorectal cancer cells in vivo. These results suggest that adenovirus-mediated p73beta and p51A/p63gamma transfer are potential novel approaches for the treatment of human cancers, particularly for tumors that are resistant to p53 gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / genetics*
  • Carcinogenicity Tests
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy*
  • DNA-Binding Proteins / genetics
  • Doxorubicin / pharmacology
  • Genes, Tumor Suppressor
  • Genes, p53*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Humans
  • Membrane Proteins*
  • Mice
  • Mice, Nude
  • Nuclear Proteins / genetics
  • Phosphoproteins / genetics
  • Trans-Activators / genetics
  • Transcription Factors
  • Transduction, Genetic / methods
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Proteins

Substances

  • Antineoplastic Agents
  • CKAP4 protein, human
  • DNA-Binding Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp63 protein, mouse
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • p73 protein, human
  • Doxorubicin