文章基本信息

标题：CRIF1 as a potential target to improve the radiosensitivity of osteosarcoma
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作者：Qian Ran ; Qian Ran ; Feng Jin 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：41
页码：20511-20516
DOI：10.1073/pnas.1906578116
出版社：The National Academy of Sciences of the United States of America
摘要：Resistance to ionizing radiation (IR), which is a conventional treatment for osteosarcoma that cannot be resected, undermines the efficacy of this therapy. However, the mechanism by which IR induces radioresistance in osteosarcoma is not defined. Here, we report that CR6-interacting factor-1 (CRIF1) is highly expressed in osteosarcoma and undergoes nuclear-cytoplasmic shuttling of cyclin-dependent kinase 2 (CDK2) after IR. Osteosarcoma cells lacking CRIF1 show increased sensitivity to IR, which is associated with delayed DNA damage repair, inactivated G1/S checkpoint, and mitochondrial dysfunction. CRIF1 interacts with the DNA damage checkpoint regulator CDK2, and CRIF1 and CDK2 colocalize in the nucleus after IR. Nuclear localization of CDK2 is associated with phosphorylation changes that promote DNA repair and activation of the G1/S checkpoint. CRIF1 knockdown synergized with IR in an in vivo osteosarcoma model, leading to tumor regression. Based on these findings, we identify CRIF1 as a potential therapeutic target in osteosarcoma that can increase the efficacy of radiotherapy. More broadly, our findings may provide insights into the mechanism for other types of radioresistant cancers and be exploited for therapeutic ends..
关键词：CDK2 ; CRIF1 ; radiotherapy ; osteosarcoma ; radioresistance