UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGCip in hepatocellular carcinoma  

作　　者：Junjie Xu Lin Ji Yeling Ruan Zhe Wan Zhongjie Lin Shunjie Xia Liye Tao Junhao Zheng Liuxin Cai Yifan Wang Xiao Liang Xiujun Cai 

机构地区：[1]Key Laboratory of Laparoscopic Technology of Zhejiang Province,Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China [2]Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease,Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment,Hangzhou,China [3]Zhejiang University Cancer Center,Hangzhou,China [4]Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第6期1856-1868,共13页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China under No.81827804(to C.X.),Grant No.81772546(to C.X.),No.81902367(to XJ.),and No.82072625(to L.X.);China Postdoctoral Science Foundation under Grant No.2020M671755(to X.J.);Natural Science Foundation of Zhejiang Province under Grant No.LY15H160014(to C.L.);Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases under Grant No.2018E50003(to C.X.);Key Research and Development Project of Zhejiang Province under Grant No.2018C03083(to C.X.),and 2020C03122(to W.Y.);Health innovation Talent Support Project of Zhejiang Medical and Health Science and Technology Plan under Grant No.2021447581(to XJ.).

摘　　要：The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often occurs,largely limits its efficacy.Sorafenib was found to target the electron transport chain complexes,which results in the generation of reactive oxygen species(ROS).To maintain sorafenib resistance and further facilitate tumor progression,cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death.In the present study,we investigated the roles of ROS in sorafenib resistance,and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells.Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib.However,cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells.Further investigation attributed this finding to decreased mitochondrial biogenesis,likely caused by the accelerated degradation of peroxisome proliferator-activated receptor y coactivator ip(PGC1P).Mechanistic dissection showed that upregulated UBQLN1 induced PGCip degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.Furthermore,clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival.In conclusion,we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance,which may offer new therapeutic targets and strategies for HCC patients.

关 键 词：HOMEOSTASIS RESISTANCE OVERCOME 

分 类 号：R735.7[医药卫生—肿瘤]