Laboratory of Veterinary Hygiene, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515, Japan.
Laboratory of Veterinary Hygiene, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515, Japan.
Biochem Biophys Res Commun. 2023 Feb 19;645:1-9. doi: 10.1016/j.bbrc.2023.01.035. Epub 2023 Jan 13.
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 ATR-Chk1 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.
内吞作用在癌症增殖和转移中起着重要作用。最近的研究积累了证据，表明内吞作用抑制剂抑制体外和体内增殖和迁移。此外，内吞作用抑制已被证明诱导细胞凋亡，但其机制在很大程度上尚不清楚。在这项研究中，我们发现内吞作用抑制剂 dynasore 可降低多种癌细胞系的细胞活力，尤其是血液系统癌症。Dynasore 诱导大量细胞凋亡和 S 期进展延迟。此外，dynasore 激活了 ATR-Chk1 DNA 损伤反应，这表明 DNA 复制应激引起了单链 DNA 的暴露。此外，ATR 抑制剂使 dynasore 诱导的细胞凋亡更加敏感。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，这是针对癌症的遗传毒性化学疗法的共同机制，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。
