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.

中文翻译：

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辛伐他汀通过抑制HIF-1α/PPAR-γ/ PKM2介导的糖酵解，使肝癌细胞对索拉非尼敏感。

背景技术肝细胞癌（HCC）是一种常见的原发性恶性肿瘤，由于诊断晚，通常会发展到晚期。索拉非尼（Sora）是晚期HCC的一线药物；但是，它面临着巨大的阻力。辛伐他汀（辛伐他汀）是一种降低胆固醇的药物，据报道可抑制肿瘤生长。本研究旨在确定Sora和Sim共同治疗是否可以改善HCC中的Sora抗性。方法采用HCC细胞株LM3和建立的耐Sora耐药LM3细胞株（LM3-SR）研究Sora耐药与需氧糖酵解之间的关系。通过蛋白质印迹，流式细胞仪分析和生物医学测试分析细胞增殖，凋亡和糖酵解水平。还使用异种移植模型检查Sim在体内的作用。还通过使用激活剂和抑制剂以及慢病毒转染进行了详细的机理研究。结果我们的结果表明，对Sora的抗性与需氧糖酵解水平提高有关。此外，LM3-SR细胞对Sim的敏感性高于LM3细胞，这表明与Sora和Sim联合治疗可以增强LM3-SR细胞对Sora的敏感性。此发现可能是由于抑制了HIF-1α/PPAR-γ/ PKM2轴。结论辛伐他汀可通过抑制PKM2介导的糖酵解，抑制HIF-1α/PPAR-γ/ PKM2轴，导致HCC细胞增殖减少和凋亡增加，并使HCC细胞对Sora再次敏感。结果我们的结果表明，对Sora的抗性与需氧糖酵解水平提高有关。此外，LM3-SR细胞对Sim的敏感性高于LM3细胞，这表明与Sora和Sim联合治疗可以增强LM3-SR细胞对Sora的敏感性。此发现可能是由于抑制了HIF-1α/PPAR-γ/ PKM2轴。结论辛伐他汀可通过抑制PKM2介导的糖酵解，抑制HIF-1α/PPAR-γ/ PKM2轴，导致HCC细胞增殖减少和凋亡增加，并使HCC细胞对Sora再次敏感。结果我们的结果表明，对Sora的抗性与需氧糖酵解水平提高有关。此外，LM3-SR细胞对Sim的敏感性高于LM3细胞，这表明与Sora和Sim联合治疗可以增强LM3-SR细胞对Sora的敏感性。此发现可能是由于抑制了HIF-1α/PPAR-γ/ PKM2轴。结论辛伐他汀可通过抑制PKM2介导的糖酵解，抑制HIF-1α/PPAR-γ/ PKM2轴，导致HCC细胞增殖减少和凋亡增加，并使HCC细胞对Sora再次敏感。此发现可能是由于抑制了HIF-1α/PPAR-γ/ PKM2轴。结论辛伐他汀可通过抑制PKM2介导的糖酵解，抑制HIF-1α/PPAR-γ/ PKM2轴，导致HCC细胞增殖减少和凋亡增加，并使HCC细胞对Sora再次敏感。此发现可能是由于抑制了HIF-1α/PPAR-γ/ PKM2轴。结论辛伐他汀可通过抑制PKM2介导的糖酵解，抑制HIF-1α/PPAR-γ/ PKM2轴，导致HCC细胞增殖减少和凋亡增加，并使HCC细胞对Sora再次敏感。