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Induction of accelerated senescence by gamma radiation in human solid tumor-derived cell lines expressing wild-type
Razmik Mirzayans1, April Scott, Marybeth Cameron
1Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada. razmikm@cancerboard.ab.ca
Abstract:
Recent studies have demonstrated that p21WAF1 (now known as CDKN1A)-dependent and -independent accelerated senescence responses are a major determinant of the sensitivity of cancer cells to chemotherapeutic agents. The objective of the present study was to determine whether human solid tumor-derived cell lines that express wild-type TP53 can exhibit levels of CDKN1A induction after exposure to ionizing radiation that are sufficient to activate the accelerated senescence program. Exposure to 60Co gamma radiation (< or =8 Gy) triggered accelerated senescence in all five TP53 wild-type tumor cell lines examined, albeit to differing degrees. Three of the TP53 wild-type tumor cell lines, HCT116, A172 and SKNSH, activated the TP53 signaling pathway similarly to normal human fibroblasts, as judged by the nuclear accumulation of TP53, magnitude and duration of induction of CDKN1A mRNA and CDKN1A protein, and propensity to undergo accelerated senescence after radiation exposure. In the clonogenic survival assay, the degree of radiosensitivity of these three tumor cell lines was also in the range displayed by normal human fibroblasts. On the other hand, two other TP53 wild-type tumor cell lines, A498 and A375, did not maintain high levels of CDKN1A mRNA and CDKN1A protein at late times postirradiation and exhibited only low levels of accelerated senescence after radiation exposure. Studies with a CDKN1A knockout cell line (HCT116CDKN1A-/-) confirmed that the radiation-triggered accelerated senescence is dependent on CDKN1A function. We conclude that (1) clinically achievable doses of ionizing radiation can trigger CDKN1A-dependent accelerated senescence in some human tumor cell lines that express wild-type TP53; and (2) as previously documented for normal human fibroblasts, some TP53 wild-type tumor cell lines (e.g. HCT116, A172 and SKNSH) may lose their clonogenic potential in response to radiation-inflicted injury primarily through undergoing accelerated senescence.
Insights
Ionizing radiation can trigger CDKN1A-dependent accelerated senescence in some human tumor cell lines with wild-type TP53. This senescence response, similar to that in normal fibroblasts, can reduce tumor cell survival after radiation exposure.
Area of Science:
- Oncology
- Cell Biology
- Radiation Biology
Background:
- Accelerated senescence, influenced by CDKN1A (p21WAF1), impacts cancer cell sensitivity to chemotherapy.
- The role of CDKN1A-dependent accelerated senescence in response to ionizing radiation in solid tumors is not fully understood.
Purpose of the Study:
- To investigate if human solid tumor cell lines with wild-type TP53 can activate accelerated senescence following ionizing radiation exposure.
- To determine if this senescence activation is sufficient to impact tumor cell radiosensitivity.
Main Methods:
- Exposure of five wild-type TP53 human solid tumor cell lines to 60Co gamma radiation (<=8 Gy).
- Assessment of TP53 signaling pathway activation, CDKN1A mRNA and protein induction, and senescence.
- Clonogenic survival assays to evaluate radiosensitivity.
- Studies using a CDKN1A knockout cell line (HCT116CDKN1A-/-).
Main Results:
- All five wild-type TP53 tumor cell lines exhibited radiation-induced accelerated senescence to varying degrees.
- Three cell lines (HCT116, A172, SKNSH) showed TP53 pathway activation, CDKN1A induction, and senescence comparable to normal fibroblasts.
- These three cell lines also displayed radiosensitivity within the range of normal fibroblasts.
- Two cell lines (A498, A375) showed limited CDKN1A induction and low senescence levels post-irradiation.
- CDKN1A knockout cells confirmed the dependency of radiation-triggered senescence on CDKN1A function.
Conclusions:
- Clinically relevant doses of ionizing radiation can induce CDKN1A-dependent accelerated senescence in certain wild-type TP53 human tumor cell lines.
- Some wild-type TP53 tumor cell lines may lose clonogenic potential post-irradiation due to accelerated senescence, similar to normal fibroblasts.
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