Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib

被引：0
作者：
Hongming Pan
Zhanggui Wang
Liming Jiang
Xinbing Sui
Liangkun You
Jiawei Shou
Zhao Jing
Jiansheng Xie
Weiting Ge
Xiujun Cai
Wendong Huang
Weidong Han
机构：
[1] Sir Run Run Shaw Hospital,Department of Medical Oncology
[2] College of Medicine,Department of General Surgery
[3] Zhejiang University,Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research
[4] Laboratory of Cancer Biology,undefined
[5] Cancer Institute,undefined
[6] The Second Affiliated Hospital,undefined
[7] College of Medicine,undefined
[8] Zhejiang University,undefined
[9] Sir Run Run Shaw Hospital,undefined
[10] College of Medicine,undefined
[11] Zhejiang University,undefined
[12] Beckman Research Institute,undefined
[13] City of Hope National Medical Center,undefined
[14] Institute of Clinical Science,undefined
[15] Sir Run Run Shaw Hospital,undefined
[16] College of Medicine,undefined
[17] Zhejiang University,undefined
来源：
Scientific Reports | / 4卷
关键词：
D O I：
暂无
中图分类号：
学科分类号：
摘要：
Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PDGFR-β and its downstream Akt/mTOR and Mek/Erk signaling pathways. Cell death induced by linifanib was greatly enhanced after autophagy inhibition by the pharmacological inhibitors or siRNAs against autophagy related genes, ATG5 and ATG7, in vitro. Moreover, HCQ, an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-HCC effect of linifanib in a mouse xenograft model. In conclusion, linifanib can induce cytoprotective autophagy by suppression of PDGFR-β activities in HCC cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of linifanib in the treatment of HCC patients.
引用
收藏
相关论文
共 72 条
[11]  
Heldin CH(2014)Hepatocellular Carcinoma: Reasons for Phase III Failure and Novel Perspectives on Trial Design Clin Cancer Res 20 2072-2079
[12]  
Westermark B(2014)An overview of autophagy: morphology, mechanism and regulation Antioxidants & redox signaling 20 460-473
[13]  
Ikeda AK(2012)Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells Cancer Lett 314 232-243
[14]  
Zhou J(2012)Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer PLoS One 7 e42265-557
[15]  
Toh HC(2012)Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma Int J Cancer 131 548-5952
[16]  
Llovet JM(2010)The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex Cancer Res 70 5942-544
[17]  
Hernandez-Gea V(2011)EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells PLoS One 6 e18691-963
[18]  
Parzych KR(2012)Guidelines for the use and interpretation of assays for monitoring autophagy Autophagy 8 445-436
[19]  
Klionsky DJ(2011)The multiple roles of autophagy in cancer Carcinogenesis 32 955-4641
[20]  
Xu Y(2010)Selective degradation of p62 by autophagy Semin Immunopathol 32 431-1025
12345678