Autophagy 2011 Oct;7 (10): 1159-72. [IF:6.643]
Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.
Shi YH , Ding ZB , Zhou J , Hui B , Shi GM , Ke AW , Wang XY , Dai Z , Peng YF , Gu CY , Qiu SJ , Fan J .
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
上海复旦大学，肝癌研究所，中山医院肝脏外科
Abstract
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.
摘要
索拉菲尼是一种有效的多激酶抑制剂，已经被用于晚期肝癌（HCC）治疗的标准方案。虽然索拉菲尼杀伤肿瘤的直接作用机制是明确的，但对其耐药的具体机制还不太清楚。我们的研究显示，索拉菲尼诱导人肝癌细胞凋亡和自体吞噬的机制与内质网应激和独立的MEK1/2-ERK1/2途径有关。索拉非尼诱导内质网应激从而上调IRE1信号是产生自体吞噬的关键。与此同时，自体吞噬的激活又缓解了内质网应激诱导的细胞死亡。不管是用药物抑制剂或是敲除自体吞噬必须基因来抑制自体吞噬都增强了索拉非尼处理过的肝癌细胞株的死亡。更关键的是，索拉非尼与自体吞噬抑制剂氯喹联用在体内和体外都更显著抑制肝癌细胞。
这些发现说明内质网应激和自体吞噬都和索拉非尼诱导的肝癌细胞死亡有关。自体吞噬调节剂与分子靶向治疗联用有望成为肝癌治疗的新策略。
