Back to Search
Start Over
A Dominant Role for p53-Dependent Cellular Senescence in Radiosensitization of Human Prostate Cancer Cells
- Source :
- Cell Cycle. 6:595-605
- Publication Year :
- 2007
- Publisher :
- Informa UK Limited, 2007.
-
Abstract
- 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.
- Subjects :
- Male
Senescence
Prostatic Neoplasms
Dose-Response Relationship, Radiation
Cell Biology
Nutlin
Biology
medicine.disease
Radiation Tolerance
chemistry.chemical_compound
Prostate cancer
chemistry
DU145
Cell Line, Tumor
Cancer cell
Cancer research
medicine
Humans
Radiosensitivity
Tumor Suppressor Protein p53
Clonogenic assay
Molecular Biology
Mitotic catastrophe
Cellular Senescence
Developmental Biology
Subjects
Details
- ISSN :
- 15514005 and 15384101
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Cycle
- Accession number :
- edsair.doi.dedup.....4cf068f0761b55301c1b0a7ef483b98c