Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Autophagy. 2011 Oct;7(10):1159-72. doi: 10.4161/auto.7.10.16818. Epub 2011 Oct 1.
Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.
索拉非尼是一种有效的多激酶抑制剂，已被认为是晚期肝细胞癌（HCC）患者的标准系统治疗方法。然而，索拉非尼介导的肿瘤致死的直接功能机制仍有待充分描述，药物耐药的确切机制在很大程度上尚不清楚。在这里，我们通过涉及内质网（ER）应激且不依赖于 MEK1/2-ERK1/2 途径的机制，表明索拉非尼在人 HCC 细胞中诱导凋亡和自噬。来自索拉非尼诱导的 ER 应激的 IRE1 信号的上调对于自噬的诱导至关重要。此外，自噬的激活缓解了 ER 应激诱导的细胞死亡。使用药理学抑制剂或必需的自噬基因敲低抑制自噬均增强了索拉非尼处理的 HCC 细胞系中的细胞死亡。至关重要的是，索拉非尼与自噬抑制剂氯喹的联合使用在体内和体外均在 HCC 中产生了更明显的肿瘤抑制作用。这些发现表明，内质网应激和自噬均参与了索拉非尼在 HCC 细胞中诱导的细胞死亡。自噬调节与分子靶向治疗的联合是治疗 HCC 的一种有前途的治疗策略。
