The endocytosis inhibitor dynasore induces a DNA damage response pathway that can be manipulated for enhanced apoptosis
The endocytosis inhibitor dynasore induces a DNA damage response pathway that can be manipulated for enhanced apoptosis
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DOI：
10.1016/j.bbrc.2023.01.035
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发表时间：
2023-01-17
影响因子：
3.1
通讯作者：
Iwata, Hiroyuki
中科院分区：
文献类型：
--
作者：
Suemura, Miki;Shibutani, Shusaku;Iwata, Hiroyuki
内吞作用在肿瘤的增殖和转移中起着重要的作用。最近的研究已经积累了证据，内吞抑制剂抑制在体外和体内的增殖和迁移。此外，内吞抑制已被证明可诱导细胞凋亡，但其机制在很大程度上仍不清楚。在这项研究中，我们发现内吞抑制剂dynasore导致多种癌细胞系中细胞活力降低，特别是在造血系统癌症中。Dynasore诱导大量细胞凋亡和S期进展延迟。此外，dynasore激活了ATRChk1 DNA损伤反应，这表明DNA复制应激诱导的单链DNA暴露。此外，ATR抑制剂敏化dynasore诱导的细胞凋亡。这些发现表明，内吞作用抑制剂可能具有抑制DNA复制的能力，这是靶向癌症的遗传毒性化疗的常见机制，并且内吞作用抑制剂的抗癌作用可能被DNA损伤反应抑制剂敏化。(c)2023爱思唯尔公司All rights reserved.
Endocytosis has been shown to play an important role in cancer proliferation and metastasis. Recent studies have accumulated evidence that endocytosis inhibitors suppress in vitro and in vivo proliferation and migration. In addition, endocytosis inhibition has been shown to induce apoptosis, but its mechanism remains largely unclear. In this study, we found that the endocytosis inhibitor dynasore causes a cell viability reduction in multiple cancer cell lines, especially in hematopoietic cancers. Dynasore induced massive apoptosis and an S-phase progression delay. In addition, dynasore activated the ATRChk1 DNA damage response, which suggests a single-stranded DNA exposure induced by DNA replication stress. Furthermore, an ATR inhibitor sensitized the dynasore-induced apoptosis. These findings suggest that endocytosis inhibitors may have an ability to suppress DNA replication, a common mechanism of genotoxic chemotherapies targeting cancer, and that the anti-cancer effects of endocytosis inhibitors may be sensitized by DNA damage response inhibitors.(c) 2023 Elsevier Inc. All rights reserved.