Jiao Feng1, Weiqi Dai2,3,4,5,6, Yuqing Mao7, Liwei Wu1, Jingjing Li1,8, Kan Chen1, Qiang Yu1, Rui Kong1, Sainan Li1, Jie Zhang1,9, Jie Ji1, Jianye Wu8, Wenhui Mo10, Xuanfu Xu10, Chuanyong Guo11. 1. Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing'an District, Shanghai, 200072, China. 2. Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing'an District, Shanghai, 200072, China. dai_yue@163.com. 3. Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, 200060, China. dai_yue@163.com. 4. Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China. dai_yue@163.com. 5. Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China. dai_yue@163.com. 6. Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200336, China. dai_yue@163.com. 7. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China. 8. Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, 200060, China. 9. Shanghai Tenth Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai, 200072, China. 10. Department of Gastroenterology, Shidong Hospital of Shanghai, Shanghai, 200433, China. 11. Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing'an District, Shanghai, 200072, China. guochuanyong@hotmail.com.
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.
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 Simco-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 Simcould 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.