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Rapamycin suppresses the PI3K/AKT/mTOR signaling pathway by targeting SIRT1 in esophageal cancer
Tao Liu1,2, Xiangsen Liang2, Yu Sun2
1Department of Cardiothoracic Surgery, Guangxi International Zhuang Medical Hospital, Nanning, Guangxi 530201, P.R. China.
Abstract:
Rapamycin, a secondary metabolite produced by Streptomyces hygroscopicus, is known for its pharmacological effects, especially antitumor and immunosuppressive activities. However, the antitumoral effects of rapamycin in human esophageal cancer (EC) are still poorly understood. To investigate the potential of rapamycin in EC treatment, sirtuin 1 (SIRT1) mRNA expression was quantified in the tissue of patients with EC or in EC cell lines using reverse transcription-quantitative PCR. The protein levels of SIRT1 and PI3K/AKT/mTOR were measured via western blotting. Furthermore, cell viability, migration and invasion were investigated by Cell Counting Kit-8, wound healing and Transwell assays, respectively. The present results suggested that SIRT1 expression was upregulated in EC. In vitro, the inhibitory effect of rapamycin on cell viability in EC was strengthened or weakened after small interfering (si)-SIRT1 or pcDNA3.1/SIRT1 transfection. Furthermore, SIRT1 rescued the inhibitory effect of rapamycin on the migration and invasion of EC cells. In vivo, si-SIRT1 or SIRT1 overexpression in mice could enhance or rescue the inhibitory effects of rapamycin on tumor growth. In addition, SIRT1 transfection rescued the decreased level of phosphorylated (p)-PI3K, p-AKT and p-mTOR induced by rapamycin treatment. Taken together, the present results suggested that rapamycin suppressed the cell viability, migration, invasion and PI3K/AKT/mTOR signaling pathway in EC by negatively regulating SIRT1.
Insights
Rapamycin
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Rapamycin exhibits antitumor and immunosuppressive properties.
- The role of rapamycin in human esophageal cancer (EC) treatment is not well understood.
- Sirtuin 1 (SIRT1) is implicated in various cellular processes and cancer.
Purpose of the Study:
- To investigate the antitumoral effects of rapamycin in human esophageal cancer (EC).
- To explore the role of sirtuin 1 (SIRT1) in mediating rapamycin's effects on EC.
- To analyze the impact of rapamycin and SIRT1 modulation on the PI3K/AKT/mTOR pathway in EC.
Main Methods:
- Quantification of SIRT1 mRNA expression using reverse transcription-quantitative PCR.
- Measurement of SIRT1 and PI3K/AKT/mTOR protein levels via western blotting.
- Assessment of cell viability, migration, and invasion using CCK-8, wound healing, and Transwell assays.
- In vivo studies using mouse models with manipulated SIRT1 expression.
Main Results:
- SIRT1 expression was found to be upregulated in EC tissues and cell lines.
- Rapamycin's inhibitory effects on EC cell viability, migration, and invasion were modulated by altering SIRT1 levels.
- SIRT1 overexpression rescued rapamycin's inhibitory effects, while SIRT1 knockdown enhanced them.
- Rapamycin treatment led to decreased phosphorylation of PI3K, AKT, and mTOR, which was reversed by SIRT1 transfection.
Conclusions:
- Rapamycin demonstrates potential in suppressing esophageal cancer progression.
- The study identifies SIRT1 as a key regulator in rapamycin's antitumoral mechanism in EC.
- Rapamycin exerts its effects by negatively regulating SIRT1 and inhibiting the PI3K/AKT/mTOR signaling pathway.
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