中科院近代物理研究所辐射医学研究室与日本国立放射医学研究中心科研人员开展的合作研究发现，肿瘤细胞染色体末端端粒的保护状态直接影响其对重离子辐射的敏感性。

端粒是细胞染色体末端的高度重复序列，对染色体结构起着重要的维持与保护作用。端粒长度的缩短及其结构的异常变化是细胞衰老以及死亡的一个重要诱因。在正常细胞中，端粒由于端粒酶的失活随着每次细胞分裂逐渐变短；而在肿瘤细胞中，由于端粒酶的异常激活，其端粒长度可以不随细胞分裂而缩短。这是肿瘤细胞维持其增殖潜能的一个重要机制。

科研人员研究发现，重离子辐照后的MCF-7及HeLa细胞尽管其DNA损伤能够得到快速修复，但还是会最终走向细胞死亡。同时还发现，通过抑制DNA双链断裂修复系统非同源末端连接中一个重要的修复因子DNA-PKcs的活性，DNA损伤依然得到了快速修复，但细胞的辐射敏感性却大大增强。分析表明，这可能是由于DNA-PKcs抑制引起的端粒末端保护状态改变所引起的。

为此，研究人员通过建立端粒缩短的肿瘤细胞株等方法，确定了肿瘤细胞受到重离子辐照后可能由于端粒末端正常结构的改变而激活DNA损伤应激，从而最终走向细胞死亡。

原文检索：

DNA-PKcs Inhibition Sensitizes Cancer Cells to Carbon-Ion Irradiation via Telomere Capping Disruption

Heavy-ion irradiation induces a higher frequency of DNA double strand breaks (DSBs) which must be properly repaired. Critical shortening of telomeres can trigger DNA damage responses such as DSBs. Telomeres are very sensitive to oxidative stress such as ionizing radiation. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the central component in the non-homologous end joining (NHEJ) repair complex and participates in telomere maintenance. Therefore, it is expected to enhance the cell killing effect of heavy-ion irradiation via DNA-PKcs inhibition. To test this hypothesis, cellular radiosensitivity was measured by the clonal genetic assay. DNA damage repair was relatively quantified by long PCR. Apoptosis was quantified by flow-cytometric analysis of annexin V/PI double staining, and senescence was analyzed by galactosidase activity. Telomere length was semi-quantified by real-time PCR. P53 and p21 expression was determined by western blotting. Our data demonstrated that MCF-7 and HeLa cells with DNA-PKcs inhibition were more susceptible to carbon-ion irradiation than Those without DNA-PKcs inhibition. Even though NHEJ was inhibited by the DNA-PKcs specific inhibitor, NU7026, most DNA damage induced by carbon-ion irradiation was repaired within 24 hours after irradiation in both cell lines. However, potential lethal damage repair (PLDR) could not restore cellular inactivation in DNA-PKcs inhibited cells. MCF-7 cells showed extensive senescence and accelerated telomere length reduction, while HeLa cells underwent significant apoptosis after irradiation with NU7026 incubation. In addition, both cell lines with shorter telomere were more susceptible to carbon-ion radiation. Our current data suggested that DNA-PKcs inhibition could enhance cellular sensitivity to carbon-ion radiation via disturbing its functional role in telomere end protection. The combination of DNA-PKcs inhibition and carbon-ion irradiation may be an efficient method of heavy-ion therapy.
 

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