Sequential Transformation of Mesenchymal Stem Cells is Associated with Increased Radiosensitivity and Reduced DNA Repair Capacity
| Autor: | Susan C Short, Christine Martindale, M. Worku, Naomi Fersht, J. M. Funes |
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| Rok vydání: | 2013 |
| Předmět: |
Time Factors
Radiation Cell cycle checkpoint DNA Repair DNA repair Mesenchymal stem cell Biophysics Apoptosis Mesenchymal Stem Cells Cell Cycle Checkpoints Transfection G2-M DNA damage checkpoint Biology Radiation Tolerance Cell Line Cell biology Transduction (genetics) Cell Transformation Neoplastic Humans Radiology Nuclear Medicine and imaging Telomerase reverse transcriptase Radiosensitivity DNA Damage Signal Transduction |
| Zdroj: | Radiation Research. 179:698-706 |
| ISSN: | 1938-5404 0033-7587 |
| DOI: | 10.1667/rr2998.1 |
| Popis: | We used sequentially transformed mesenchymal stem cells to investigate how the events that lead to tumorigenicity influence the cellular response to radiation. Bone marrow derived SH2(+), SH4(+), Stro-1(+) mesenchymal stem cells (MSC) were transformed stepwise by retroviral transfection of hTERT, HPV-16 E6 and E7, SV40 small T antigen and oncogenic H-ras. Cells at three different stages of transformation were irradiated and compared using assays for cytotoxicity, apoptosis, DNA double-strand break (DSB) repair and checkpoint signaling. The effects of inhibition of cell cycle checkpoint signaling on radiosensitivity were investigated using RNA interference. During stepwise transformation, specifically after HPV-16 E6 and E7 transduction, MSCs became more sensitive to radiation. This was associated with increased residual DNA DSB at 24 h and increased apoptosis. Enhanced checkpoint signaling occurred during transformation and there was a differential effect of checkpoint targeting in cells at different stages; Chk1 knockdown enhanced radiosensitivity in all cells while Chk2 knockdown only affected non-transformed cells. These data show that transformation of MSC is associated with a reduction in DNA DSB repair capacity and increased radiosensitivity. Up-regulation of checkpoint signaling does not overcome this and the effect of checkpoint inhibition may change with transformation status. |
| Databáze: | OpenAIRE |
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