International journal of radiation oncology, biology, physics, 2010-06, Vol.77 (2), p.566-574
2010
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- Autor(en) / Beteiligte
- Titel
- Depletion of Securin Induces Senescence After Irradiation and Enhances Radiosensitivity in Human Cancer Cells Regardless of Functional p53 Expression
- Ist Teil von
- International journal of radiation oncology, biology, physics, 2010-06, Vol.77 (2), p.566-574
- Ort / Verlag
- New York, NY: Elsevier Inc
- Erscheinungsjahr
- 2010
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- Purpose Radiotherapy is one of the best choices for cancer treatment. However, various tumor cells exhibit resistance to irradiation-induced apoptosis. The development of new strategies to trigger cancer cell death besides apoptosis is necessary. This study investigated the role of securin in radiation-induced apoptosis and senescence in human cancer cells. Methods and Materials Cell survival was determined using clonogenic assays. Western blot analysis was used to analyze levels of securin, caspase-3, PARP, p53, p21, Rb, γ-H2AX, and phospho-Chk2. Senescent cells were analyzed using a β-galactosidase staining assay. A securin-expressed vector (pcDNA-securin) was stably transfected into securin-null HCT116 cells. Securin gene knockdown was performed by s mall interfering RNA and small hairpin RNA in HCT116 and MDA-MB-231 cells, respectively. Results Radiation was found to induce apoptosis in securin wild type HCT116 cells but induced senescence in securin-null cells. Restoration of securin reduced senescence and increased cell survival in securin-null HCT116 cells after irradiation. Radiation-induced γ-H2AX and Chk2 phosphorylation were induced transiently in securin-wild-type cells but exhibited sustained activation in securin-null cells. Securin gene knockdown switches irradiation-induced apoptosis to senescence in both HCT116 p53-null and MDA-MB-231 cells. Conclusions Our results demonstrated that the level of securin expression plays a determining role in the radiosensitivity and fate of cells. Depletion of securin impairs DNA repair after irradiation, increasing DNA damage and promoting senescence in the residual surviving cells regardless of functional p53 expression. The knockdown of securin may contribute to a novel radiotherapy protocol for the treatment of human cancer cells that are resistant to irradiation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0360-3016eISSN: 1879-355XDOI: 10.1016/j.ijrobp.2009.12.013Titel-ID: cdi_osti_scitechconnect_21372310
- Format
- –
- Schlagworte
- ANIMAL CELLS, APOPTOSIS, Apoptosis - physiology, Apoptosis - radiation effects, Biological and medical sciences, BIOLOGICAL RECOVERY, BIOLOGICAL REPAIR, Blotting, Western, Caspase 3 - metabolism, Cell Line, Tumor - radiation effects, Cellular Senescence - physiology, Cellular Senescence - radiation effects, Checkpoint Kinase 2, CHEMICAL REACTIONS, Colony-Forming Units Assay - methods, Cyclin-Dependent Kinase Inhibitor p21 - metabolism, DISEASES, DNA REPAIR, Gene Knockdown Techniques - methods, HCT116 Cells - radiation effects, Hematology, Oncology and Palliative Medicine, Histones - metabolism, Humans, Medical sciences, MEDICINE, Neoplasm Proteins - deficiency, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, NEOPLASMS, NUCLEAR MEDICINE, ORGANIC COMPOUNDS, p53, PHOSPHORYLATION, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases - metabolism, Protein-Serine-Threonine Kinases - metabolism, PROTEINS, Radiation therapy and radiosensitizing agent, Radiation Tolerance - physiology, RADIOLOGY, RADIOLOGY AND NUCLEAR MEDICINE, RADIOSENSITIVITY, RADIOTHERAPY, REPAIR, Retinoblastoma Protein - metabolism, Securin, Senescence, SENSITIVITY, THERAPY, Treatment with physical agents, Treatment. General aspects, TUMOR CELLS, Tumor Suppressor Protein p53 - metabolism, Tumors