Suppression of SREBP-1 Expression by Simvastatin Decreases Visfatin-Induced Chemoresistance to Sunitinib in Human Renal Carcinoma 786-O Cells

• Published in: Life (Basel, Switzerland) Switzerland), 2022-11, Vol.12 (11), p.1890
• Main Authors: Chen, Te-Chuan, Huang, Chen-Wei, Lo, Chih-Yu, Chen, Cheng-Nan, Chang, Shun-Fu, Chen, Yih-Yuan
• Format: Article
• Language: English
• Subjects: Adipocytes; AKT protein; Antibiotics; Antibodies; Antilipemic agents; Body fat; Cancer; Cancer therapies; Carcinoma; Carcinoma, Renal cell; Cell culture; Cell growth; Chemoresistance; Chemotherapy; Cytotoxicity; Development and progression; Drug resistance; Drug therapy; Gene expression; Health aspects; Inactivation; Kinases; Lipids; Medical prognosis; Metastasis; mRNA; Multiple myeloma; Obesity; Pharmaceutical research; Protein binding; Proteins; Reactive oxygen species; Renal cell carcinoma; RNA; Simvastatin; siRNA; SREBP-1; Sterol regulatory element-binding protein; sunitinib; Testing; Toxicity; Transcription factors; Transferases; Tumor cells; Tumors; Variance analysis; visfatin
• ISSN: 2075-1729; 2075-1729
• DOI: 10.3390/life12111890

The resistance of renal cell carcinoma (RCC) to sunitinib impedes the success of chemotherapy in cancer treatment. Although several sunitinib resistance mechanisms have been proposed, little is known concerning the impact of obesity and adipokines in RCC cells. The upregulation of sterol-regulatory element-binding protein-1 (SREBP-1) has been reported to modulate the progression of tumor cells. The present study investigated the effect of visfatin on sunitinib-induced cytotoxicity in RCC cells through SREBP-1 expression. We found that visfatin-induced Akt and p70S6K activation increased SREBP-1 expression in 786-O cells. The visfatin-induced SREBP-1 mRNA and protein levels were attenuated through the inactivation of Akt and p70S6K by pharmacological inhibitors. In addition, the SREBP-1 knockdown using siRNA enhanced the cytotoxic effects of sunitinib. Our results also revealed the roles of simvastatin in attenuating the effects of visfatin on 786-O cells by inhibiting the production of reactive oxygen species. In particular, simvastatin co-treatment increased the cell cytotoxicity of sunitinib in visfatin-treated 786-O cells, which were associated with down-regulation of SREBP-1 expression. Our results suggest an important role of SREBP-1 in visfatin-induced drug resistance of RCC cells to sunitinib. The cytotoxic mechanism of simvastatin on RCC cells may provide a new strategy to improve therapeutic outcomes for the RCC treatment.