Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Journal of Experimental & Clinical Cancer Research

Jianye Wu¹  Yuqing Mao²  Jiao Feng³  Jie Ji³  Chuanyong Guo³  Liwei Wu³  Qiang Yu³  Jie Zhang³  Weiqi Dai³  Sainan Li³  Jingjing Li³  Kan Chen³  Rui Kong³  Xuanfu Xu⁴  Wenhui Mo⁴ 

[1] Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine;Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine;Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine;Department of Gastroenterology, Shidong Hospital of Shanghai;

关键词: Sorafenib resistance;    Simvastatin;    Glycolysis;    Hepatocellular carcinoma;    PKM2;    HIF-1α;   

DOI  :  10.1186/s13046-020-1528-x

来源: DOAJ

【 摘 要 】

Abstract Background Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections. Results Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

【 授权许可】

Unknown