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.
Highlights
Gastric cancer (GC) remains the most common cancer worldwide, and is responsible for 1,033,701 new cases, and an estimated 782,685 deaths occurred worldwide in 20181
Using univariate Cox regression analysis, we found that depth of tumor infiltration (p = 0.03), local lymph node metastasis (p < 0.001), clinical stage, tumor grade (p = 0.044), and Sirtuin 1 (SIRT1) expression levels (p < 0.001) were significantly associated with the overall survival of gastric cancer (GC) patients
The correlation between SIRT1 expression levels and the prognosis of GC patients treated with a 5-FUbased regimen suggests that SIRT1 may be associated with the patient response to chemotherapy
Summary
Gastric cancer (GC) remains the most common cancer worldwide, and is responsible for 1,033,701 new cases, and an estimated 782,685 deaths occurred worldwide in 20181. Despite the recent increase in therapeutic options, combination of 5-fluorouracil (5-FU) and cisplatin remains the generally accepted first-line chemotherapy for GC patients[2]. Due to the development of chemoresistance, the above-mentioned chemotherapy typically fails and thereby promotes GC recurrence in patients[2,3]. Tumor-initiating cells proliferate, differentiate, and produce all cell types found in a particular tumor; they are named cancer stem cells (CSCs)[4]. Compelling evidence has emerged, indicating that the persistence of CSCs is responsible for treatment failure due to the enhanced chemoresistance[4,5]. It has been recently reported that CSCs are enriched in response to chemotherapy, which further links CSCs with chemoresistance[6,7]. The plasticity of CSCs has motivated efforts to identify epigenetic targets to eliminate cancer stemness and improve chemotherapeutic responses
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