Ionizing radiation-induced responses in human cells with differing TP53 status.
Ionizing radiation-induced responses in human cells with differing TP53 status.
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DOI：
10.3390/ijms141122409
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发表时间：
2013-11-13
影响因子：
5.6
通讯作者：
Murray D
中科院分区：
文献类型：
--
作者：
Mirzayans R;Andrais B;Scott A;Wang YW;Murray D
电离辐射在人类细胞中引发多种反应，包括细胞凋亡、坏死、应激诱导的早衰、自噬和内源多倍体(如多核)。在克隆存活实验中，这些反应大多会导致克隆形成能力的丧失。然而，在癌症放射治疗中，并不是所有的克隆细胞死亡模式都必然对治疗结果有利。例如，sips和自噬之间的串扰被认为影响了肿瘤细胞维持长期生长抑制状态的能力，不幸的是，这种状态可能会导致肿瘤再生和疾病复发。同样，内多倍体巨细胞能够分离成接近二倍体的后代，继续有丝分裂活动。在此，我们回顾了p53和p21WAF1抑癌基因在决定人成纤维细胞(正常和Li-Fraumeni综合征)和实体肿瘤细胞在电离辐射后的命运中所扮演的角色的最新知识。此外，我们还讨论了受p53调控的癌基因Wip1在辐射后DNA损伤反应的时间调控中的重要作用及其对p53动态的贡献。这篇文章强调了DNA损伤反应的复杂性，并为重新思考癌细胞对治疗药物耐药的性质提供了动力。
Ionizing radiation triggers diverse responses in human cells encompassing apoptosis, necrosis, stress-induced premature senescence (SIPS), autophagy, and endopolyploidy (e.g., multinucleation). Most of these responses result in loss of colony-forming ability in the clonogenic survival assay. However, not all modes of so-called clonogenic cell “death” are necessarily advantageous for therapeutic outcome in cancer radiotherapy. For example, the crosstalk between SIPS and autophagy is considered to influence the capacity of the tumor cells to maintain a prolonged state of growth inhibition that unfortunately can be succeeded by tumor regrowth and disease recurrence. Likewise, endopolyploid giant cells are able to segregate into near diploid descendants that continue mitotic activities. Herein we review the current knowledge on the roles that the p53 and p21WAF1 tumor suppressors play in determining the fate of human fibroblasts (normal and Li-Fraumeni syndrome) and solid tumor-derived cells after exposure to ionizing radiation. In addition, we discuss the important role of WIP1, a p53-regulated oncogene, in the temporal regulation of the DNA damage response and its contribution to p53 dynamics post-irradiation. This article highlights the complexity of the DNA damage response and provides an impetus for rethinking the nature of cancer cell resistance to therapeutic agents.
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