Department of Biochemistry, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea.
Anticancer Res. 2020 Dec;40(12):6891-6897. doi: 10.21873/anticanres.14712.
BACKGROUND/AIM: Cellular senescence is an important tumor-suppressive mechanism that arrests the cell cycle of damaged cells after diverse stresses. This study aimed to elucidate the role of mitochondrial glutamine (Gln) metabolism in senescence cell-fate decision after DNA damage.
β-galactosidase staining was used to determine senescence induction. The mechanistic target of rapamycin (mTOR) activity and p21 expression were examined by western blot. Cell proliferation and clonogenic growth were evaluated.
Inhibition of mitochondrial Gln metabolism suppressed DNA damage-induced senescence, whereas increased Gln anaplerosis resulted in a profound induction of senescence. Mechanistically, Gln anaplerosis mediated senescence induction by activating mTOR signaling upon DNA damage. Importantly, enhancing Gln anaplerosis could reduce the emergence of proliferative subpopulations of cancer cells after exposure to non-lethal doses of chemotherapeutic agents.
Mitochondrial Gln metabolism is an important regulator of DNA damage-induced senescence, which may be used for developing effective therapeutic approaches.
背景/目的：细胞衰老（cellular senescence）是一种重要的肿瘤抑制机制，它可以在多种应激后阻止受损细胞的细胞周期。本研究旨在阐明线粒体谷氨酰胺（glutamine，Gln）代谢在 DNA 损伤后衰老细胞命运决定中的作用。
采用β-半乳糖苷酶染色来确定衰老的诱导。通过 Western blot 检测雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）的活性和 p21 的表达。评估细胞增殖和集落形成生长。
抑制线粒体 Gln 代谢可抑制 DNA 损伤诱导的衰老，而增加 Gln 氨甲酰化则会导致明显的衰老诱导。机制上，Gln 氨甲酰化通过在 DNA 损伤时激活 mTOR 信号来介导衰老诱导。重要的是，在暴露于非致死剂量的化疗药物后，增强 Gln 氨甲酰化可以减少癌细胞增殖亚群的出现。
线粒体 Gln 代谢是 DNA 损伤诱导衰老的一个重要调节因子，可能用于开发有效的治疗方法。
