Sunitinib Stimulates Cellular Senescence of Gastrointestinal Stromal Tumor Cells through Inhibition of SIRT1

Abstract

Objective: Cellular senescence has been linked to the genetics of gastrointestinal stromal tumors (GISTs). The escape of gastrointestinal stromal tumor cells from senescence leads to cellular immortality and uncontrolled proliferation. Therefore, inducing senescence is considered a crucial approach for preventing the progression of gastrointestinal stromal tumors. Sunitinib, a tyrosine kinase inhibitor, has been approved as a drug for treating gastrointestinal stromal tumors and renal cell carcinoma. However, it remains unclear whether Sunitinib exerts a protective effect by inducing cellular senescence in gastrointestinal stromal tumor cells. Methods: Cells were treated with Sunitinib. Cellular senescence was assessed using the senescence-associated β-galactosidase (SA-β-gal) staining assay and a telomerase activity kit. Gene and protein expression were measured using real-time PCR and western blot analysis. Results and Discussion: We found that Sunitinib reduced cell viability in GIST-882 cells. Additionally, Sunitinib induced oxidative stress and DNA damage by increasing mitochondrial reactive oxygen species (ROS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and the phosphorylated form of histone H2AX (γH2AX). The SA-β-gal staining assay revealed that Sunitinib induced cellular senescence in GIST-882 cells by reducing telomerase activity and the expression of human telomerase reverse transcriptase (hTERT). Interestingly, the presence of the antioxidant N-acetyl-L-cysteine (NAC) abolished the effects of Sunitinib on cellular senescence, suggesting the involvement of ROS in this process. Further analysis showed that Sunitinib upregulated the expression of acetylated p53 and p21 while downregulating the expression of silent information regulator sirtuin 1 (SIRT1). Notably, overexpression of SIRT1 prevented Sunitinib-induced cellular senescence in GIST-882 cells, suggesting that SIRT1 plays a key role in this process. Conclusions: Taken together, our findings suggest that Sunitinib induces a “therapy-induced senescence” effect in gastrointestinal stromal tumors by inhibiting SIRT1.