Institute of Pathogen Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
Department of Traditional Medicine, Qilu Hospital, Shandong University, Jinan, 250012, China.
Cell Death Dis. 2020 Feb 12;11(2):115. doi: 10.1038/s41419-020-2308-4.
Chemotherapy is the standard care for patients with gastric cancer (GC); however, resistance to existing drugs has limited its success. The persistence of cancer stem cells (CSCs) is considered to be responsible for treatment failure. In this study, we demonstrated that SIRT1 expression was significantly downregulated in GC tissues, and that a low SIRT1 expression level indicated a poor prognosis in GC patients. We observed a suppressive role of SIRT1 in chemoresistance of GC both in vitro and in vivo. In addition, we found that SIRT1 eliminated CSC properties of GC cells. Mechanistically, SIRT1 exerted inhibitory activities on chemoresistance and CSC properties through FOXO3 and AMPK. Furthermore, a synergistic effect was revealed between FOXO3 and AMPK. AMPK promoted nuclear translocation of FOXO3 and enhanced its transcriptional activities. In addition, FOXO3 increased the expression level and activation of AMPKα by directly binding to its promoter and activating the transcription of AMPKα. Similar to SIRT1, low expression levels of p-AMPKα and FOXO3a are also related to the poor prognosis of GC patients. Moreover, we revealed a correlation between the expression levels of SIRT1, p-AMPKα, and FOXO3a. These findings indicated the importance of the SIRT1-AMPK/FOXO3 pathway in reversing chemoresistance and CSC properties of GC. Thus, exploring efficient strategies to activate the SIRT1-AMPK/FOXO3 pathway may lead to improving the survival of GC patients.
化疗是胃癌（GC）患者的标准治疗方法；然而，现有药物的耐药性限制了其疗效。癌症干细胞（CSCs）的持续存在被认为是导致治疗失败的原因。在本研究中，我们证明 SIRT1 表达在 GC 组织中显著下调，并且 SIRT1 低表达水平预示着 GC 患者预后不良。我们观察到 SIRT1 在体外和体内均对 GC 的化疗耐药性具有抑制作用。此外，我们发现 SIRT1 消除了 GC 细胞的 CSC 特性。在机制上，SIRT1 通过 FOXO3 和 AMPK 发挥抑制化疗耐药性和 CSC 特性的作用。此外，FOXO3 和 AMPK 之间存在协同作用。AMPK 促进 FOXO3 的核转位并增强其转录活性。此外，FOXO3 通过直接结合其启动子并激活 AMPKα 的转录来增加 AMPKα 的表达水平和激活。与 SIRT1 相似，p-AMPKα 和 FOXO3a 的低表达水平也与 GC 患者的不良预后相关。此外，我们揭示了 SIRT1、p-AMPKα 和 FOXO3a 的表达水平之间存在相关性。这些发现表明 SIRT1-AMPK/FOXO3 通路在逆转 GC 的化疗耐药性和 CSC 特性方面的重要性。因此，探索有效的策略来激活 SIRT1-AMPK/FOXO3 通路可能会提高 GC 患者的生存率。
