Abstract
Studies of radiation interaction with tumor cells often take apoptosis as the desired results. However, mitotic catastrophe and senescence are also promoted by clinically relevant doses of radiation. Furthermore, p53 is a well-known transcription factor that is closely associated with radiosensitivity and radiation-induced cell death. Therefore, we aimed to investigate the involvement of radiosensitivity, cell death modalities and p53 status in response to carbon-ion radiation (CIR) here. Isogenic human colorectal cancer cell lines HCT116 (p53+/+ and p53−/−) were irradiated with high-LET carbon ions. Cell survival was determined by the standard colony-forming assay. 53BP1 foci were visualized to identify the repair kinetics of DNA double-strand breaks (DSBs). Cellular senescence was measured by SA-β-Gal and Ki67 staining. Mitotic catastrophe was determined with DAPI staining. Comparable radiosensitivities of p53+/+ and p53−/− HCT116 colorectal cells induced by CIR were demonstrated, as well as persistent 53BP1 foci indicated DNA repair deficiency in both cell lines. Different degree of premature senescence in isogenic HCT116 colorectal cancer cells suggested that CIR-induced premature senescence was more dependent on p21 but not p53. Sustained upregulation of p21 played multifunctional roles in senescence enhancement and apoptosis inhibition in p53+/+ cells. p21 inhibition further increased radiosensitivity of p53+/+ cells. Complex cell death modalities rather than single cell death were induced in both p53+/+ and p53−/− cells after 5 Gy CIR. Mitotic catastrophe was predominant in p53−/− cells due to inefficient activation of Chk1 and Chk2 phosphorylation in combination with p53 null. Senescence was the major cell death mechanism in p53+/+ cells via p21-dependent pathway. Taken together, p21-mediated premature senescence might be used by tumor cells to escape from CIR-induced cytotoxicity, at least for a time.
Highlights
Colorectal cancer (CRC) is the fifth common malignancy and the fifth leading cause of cancer deaths in China [1]
Till day 5, Ki67 positive cells dropped to 8.6% and 19.8% in p53+/+ and p53−/− cells, respectively (Fig. 3C). These findings demonstrate that carbon-ion radiation (CIR) induces different degrees of senescence in isogenic HCT116 CRC cells
The results obtained up to now substantiate that CIR is more effective than X-rays in killing tumor cells [16]
Summary
Colorectal cancer (CRC) is the fifth common malignancy and the fifth leading cause of cancer deaths in China [1]. Radiation therapy is one of the major therapeutic strategies with effective local control and protection of normal tissues for patients with CRC. Patients experience metastasis or recurrence after radiation treatment leading to poor prognosis. Studies of therapy or radiation interactions on tumor cells often take the promotion of apoptosis as the desired cell-killing effect [2]. The significance of alternative apoptosis-independent therapeutic regimens for cancer treatment caused by mutations and/or deficiencies in the apoptotic signaling pathways have been suggested. Numerous recent studies have revealed that senescence is an important response mechanism to radiotherapy in which cancer cells escape from apoptosis and instead enter into a prolonged cell cycle arrest [3]
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