2. Academic Validation
  3. SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

  • Cell Death Dis. 2020 Feb 12;11(2):115. doi: 10.1038/s41419-020-2308-4.
Yifei An 1,  Bo Wang 2,  Xin Wang 1,  Guoying Dong 1,  Jihui Jia 1 3 4,  Qing Yang 5 6 7
Affiliations

Affiliations

  • 1 Institute of Pathogen Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
  • 2 Department of Traditional Medicine, Qilu Hospital, Shandong University, Jinan, 250012, China.
  • 3 Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
  • 4 Cancer Research Laboratory, Shandong University, Karolinska Institute Collaborative Laboratory, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
  • 5 Institute of Pathogen Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China. yangqing07@sdu.edu.cn.
  • 6 Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China. yangqing07@sdu.edu.cn.
  • 7 Cancer Research Laboratory, Shandong University, Karolinska Institute Collaborative Laboratory, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China. yangqing07@sdu.edu.cn.
PMID: 32051395 DOI: 10.1038/s41419-020-2308-4
Abstract

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.

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