A dominant role for p53-dependent cellular senescence in radiosensitization of human prostate cancer cells

Cell Cycle. 2007 Mar 1;6(5):595-605. doi: 10.4161/cc.6.5.3901. Epub 2007 Mar 18.


Because p53 inactivation may limit the effectiveness of radiation therapy for localized prostate cancer, it is important to understand how this gene regulates clonogenic survival after an exposure to ionizing radiation. Here, we show that premature cellular senescence is the principal mode of cell death accounting for the radiosensitivity of human prostate cancer cell lines retaining p53 function. Alternative stress response pathways controlled by this tumor suppressor, including cell cycle arrest, DNA damage repair, mitotic catastrophe and apoptosis, contributed significantly less to radiation-induced clonogenic death. Using a dominant negative C-terminal fragment of p53, we present the first evidence that a complete loss of endogenous p53 function is sufficient to limit the irradiation-induced senescence and clonogenic death of prostate cancer cells. Conversely, inheritance of wild-type p53 by prostate cancer cells lacking a functional allele of this gene (i.e., DU145) significantly increases clonogenic death through p53-dependent cellular senescence and apoptotic pathways. Our data provide evidence that mutations of even one p53 allele may be sufficient to alter their clonogenic fate. In addition, they support the idea that the p53 pathway can be used as a specific target for enhancing the radiosensitivity of prostate cancer cells. Activation of p53 by the drug nutlin-3 is shown to be an effective radiosensitizer of prostate cancer cells retaining functional alleles of p53 and this effect was entirely attributable to an increased induction of p53-dependent cellular senescence.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cellular Senescence / physiology
  • Cellular Senescence / radiation effects*
  • Dose-Response Relationship, Radiation
  • Humans
  • Male
  • Prostatic Neoplasms* / physiopathology
  • Prostatic Neoplasms* / radiotherapy
  • Radiation Tolerance / physiology
  • Radiation Tolerance / radiation effects*
  • Tumor Suppressor Protein p53 / physiology*
  • Tumor Suppressor Protein p53 / radiation effects*


  • Tumor Suppressor Protein p53