Dasatinib inhibits proliferation of liver cancer cells,but activation of Akt/mTOR compromises dasatinib as a cancer drug  

作　　者：Chang Liu Xiaoxia Zhu Yuqi Jia Fenqing Chi Keru Qin Jinhong Pei Chan Zhang Xiuli Mu Hongwei Zhang Xiushan Dong Jun Xu Baofeng Yu 

机构地区：[1]Department of Biochemistry and Molecular Biology,Changzhi Medical College,Changzhi 046000,China [2]Department of Biochemistry and Molecular Biology,Shanxi Medical University,Taiyuan 030001,China [3]Department of Hematology,Affiliated Tumor Hospital of Shanxi Medical University,Taiyuan 030013,China [4]Department of General Surgery,Shanxi Bethune Hospital,Taiyuan 030032,China [5]Department of General Surgery,The First Hospital of Shanxi Medical University,Taiyuan 030001,China

出　　处：《Acta Biochimica et Biophysica Sinica》2021年第7期823-836,共14页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grants from the National Natural Science Foundation of China(Nos.30901821 and 82072737);Nature Science Project of Shanxi Province,China(Nos.201701D121165 and 201901D111190);Research Project Supported by Shanxi Scholarship Council of China(No.2020-194);Key R&D Projects in Shanxi Province,China(No.201703D421023);Open Fund from Key Laboratory of Cellular Physiology(Shanxi Medical University),Ministry of Education,China(No.KLMEC/SXMU-202011);Shanxi l1331 Project5 Key Subjects Construction,China(No.1331KSC);Scientific Research Starting Foundation for Doctor of Changzhi Medical College(No.BS202007).

摘　　要：Dasatinib is a multi-target protein tyrosine kinase inhibitor.Due to its potent inhibition of Src,Abl,the platelet-derived growth factor receptor(PDGFR)family kinases,and other oncogenic kinases,it has been investigated as a targeted therapy for a broad spectrum of cancer types.However,its efficacy has not been significantly extended beyond leukemia.The mechanism of resistance to dasatinib in a wide array of cancers is not clear.In the present study,we investigated the effect of dasatinib on hepatocellular carcinoma cell growth and explored the underlying mechanisms.Our results showed that dasatinib potently inhibited the proliferation of SNU-449 cells,but not that of other cell lines,such as SK-Hep-1,even though it inhibited the phosphorylation of Src on both negative and positive regulation sites in all these cells.Dasatinib activated the phosphoinositide-dependent protein kinase1(PDK1)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling pathway in SK-Hep-1 cells,but not in SNU-449 cells.Blocking the Akt/mTOR signaling pathway strongly promoted the efficacy of dasatinib in SK-Hep-1 cells.In SNU-449 cells,dasatinib promoted apoptosis and the cleavage of caspase-3 and caspase-7,induced cell cycle arrest in the G1 phase,and inhibited the expression of Cyclin-dependent kinase(CDK4)/6/CyclinD1 complex.These findings demonstrate that dasatinib exerts its anti-proliferative effect on hepatocellular cell proliferation by blocking the Src family kinases;however,it causes Akt activation,which compromises dasatinib as an anti-cancer drug.

关 键 词：DASATINIB SNU-449 SK-Hep-1 Akt-mTOR signaling 

分 类 号：R979.1[医药卫生—药品]