Propofol inhibition of hepatocellular carcinoma via the prevention of reactive oxygen species-induced Cav1 and HO-1 activation

In this study, we showed that Propofol could effectively suppressed the growth of tumor and metastasis derived from metastatic HCC cells, and the growth of HCC patient-derived xenograft. Secondly, we delineated the effect of reactive oxygenase species (ROS) in the activation of Src/caveolin-1 (Cav1). The ROS-induced Cav1 resulted in the upregulation and nuclear translocation of heme oxygenase 1 (HO-1), resulting in HCC aggressive properties. Thirdly, we demonstrated the effect of Propofol in upregulation of mitochondrial antioxidant capacity and suppression of Cav1 expression as well as HO-1 activation in HCC cells. Lastly, we showed that Propofol did not affect the growth of normal hepatocyte, and the exclusive expression of Cav1 and HO-1 in metastatic HCC cells. These findings implicate the potential to develop anti-Cav1 and anti-HO-1 reagents without adverse effects on normal hepatocytes as a new strategy for treating HCC.

本研究证实，异丙酚（Propofol）可有效抑制转移性肝细胞癌（hepatocellular carcinoma, HCC）细胞来源的肿瘤生长与转移，以及肝细胞癌患者来源异种移植瘤（patient-derived xenograft）的生长。其次，本研究阐明了活性氧物种（reactive oxygen species, ROS）在Src激酶/小窝蛋白1（caveolin-1, Cav1）激活过程中的作用；ROS诱导的小窝蛋白1可上调血红素氧合酶1（heme oxygenase 1, HO-1）的表达并促进其核转位，进而赋予肝细胞癌侵袭性表型。再者，本研究证实，异丙酚可上调肝细胞癌细胞的线粒体抗氧化能力，同时抑制小窝蛋白1的表达与血红素氧合酶1的激活。最后，本研究发现异丙酚不会影响正常肝细胞的生长，且小窝蛋白1与血红素氧合酶1仅在转移性肝细胞癌细胞中特异性表达。上述研究结果提示，开发靶向小窝蛋白1与血红素氧合酶1且不影响正常肝细胞功能的抗肿瘤制剂，有望成为治疗肝细胞癌的全新策略。