YM155对肝癌HepG2细胞增殖和凋亡的影响
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摘要
目的:探讨YM155对肝癌HepG2细胞增殖和凋亡的影响及可能的机制。方法:采用CCK-8法检测细胞生长抑制率;应用流式细胞仪检测细胞凋亡率的变化;Western blot法检测细胞中蛋白表达的变化,实时定量RT-PCR检测survivin mRNA表达的变化。结果:YM155对人肝癌HepG2细胞的生长抑制作用呈现剂量和时间依赖性。流式细胞术结果显示,HepG2细胞凋亡率明显升高,呈现剂量依赖性。YM155可引起survivin mRNA及蛋白表达下降,而caspase-3、caspase-9和PARP蛋白表达上升。结论:YM155可以抑制人肝癌HepG2细胞的增殖并促进其凋亡,其机制可能是通过激活caspase凋亡途径来实现。
Objective:To investigate the effects of YM155 on human hepatic carcinoma cell lines HepG2 and the possible mechanisms.Methods:Cell growth inhibition rates were determined by CCK-8 assay.The apoptosis rates of HepG2 cells were analyzed by flow cytometry.The expression levels of proteins were detected by Western blot.Survivin mRNA expression was determined by real time polymerase chain reaction(RT-PCR).Results:The proliferation rate of HepG2 cells in the YM155 treated group decreased in a dose-and-time-dependent manner.FCM results showed that the apoptosis rate of HepG2 cells was increased in a dose-dependent manner.YM155 could significantly down-regulate mRNA and protein levels of survivin.It can also up-regulate caspase-3,caspase-9 and PARP protein levels.Conclusion:YM155 can inhibit proliferation and induce apoptosis of HepG2 cells through activating the apototic signal pathway of caspase.
Objective:To investigate the effects of YM155 on human hepatic carcinoma cell lines HepG2 and the possible mechanisms.Methods:Cell growth inhibition rates were determined by CCK-8 assay.The apoptosis rates of HepG2 cells were analyzed by flow cytometry.The expression levels of proteins were detected by Western blot.Survivin mRNA expression was determined by real time polymerase chain reaction(RT-PCR).Results:The proliferation rate of HepG2 cells in the YM155 treated group decreased in a dose-and-time-dependent manner.FCM results showed that the apoptosis rate of HepG2 cells was increased in a dose-dependent manner.YM155 could significantly down-regulate mRNA and protein levels of survivin.It can also up-regulate caspase-3,caspase-9 and PARP protein levels.Conclusion:YM155 can inhibit proliferation and induce apoptosis of HepG2 cells through activating the apototic signal pathway of caspase.
引文
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[14] Dizdar L,Junemann LM,Werner TA,et al.Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer[J].Oncol Lett,2018,15(3):3779-3789.
[15] Chen J,Peng SY,Yun Z,et al.The effect of YM155 on proliferation and apoptosis of osteosarcoma F5M2 cell line[J].Modern Oncology,2017,25(14):2203-2206.[陈洁,彭诗元,贠喆,等.YM155对骨肉瘤细胞系F5M2增殖和凋亡的影响[J].现代肿瘤医学,2017,25(14):2203-2206.]
[16] Hou LJ,Huang XX,Xu LN,et al.YM155 enhances docetaxel efficacy in ovarian cancer[J].Am J Transl Res,2018,10(3):696-708.
[17] Guo WZ,Zhang JK,Wang ZH,et al.Survivin inhibitor YM155 inhibits proliferation of hepatocellular carcinoma cells by inducing autophagy[J].Chinese Journal of Experimental Surgery,2017,34(7):1099-1101.[郭文治,张嘉凯,王智慧,等.生存素抑制剂YM155通过诱导自噬抑制肝癌细胞增殖[J].中华实验外科杂志,2017,34(7):1099-1101.]
[18] Means JC,Venkatesan A,Gerdes B,et al.Drosophila spaghetti and doubletime link the circadian clock and light to caspases,apoptosis and tauopathy[J].PLoS Genet,2015,11(5):e1005171.
[2] Chen X,Duan N,Zhang C,et al.Survivin and tumorigenesis:molecular mechanisms and therapeutic strategies[J].J Cancer,2016,7(3):314-323.
[3] Cai JP,Wang YD,Zhang X,et al.Expression of p16 and survivin in liver cancer and their clinical significance[J].Chin J Hepatol,2017,25(10):778-780.[蔡建平,王亚东,张晓,等.p16和survivin在肝癌中的表达及其临床意义研究[J].中华肝脏病杂志,2017,25(10):778-780.]
[4] Zhang W,Liu Y,Li YF,et al.Targeting of survivin pathways by YM155 inhibits cell death and invasion in oral squamous cell carcinoma cells[J].Cell Physiol Biochem,2016,38(6):2426-2437.
[5] Zhao X,Puszyk WM,Lu Z,et al.Small molecule inhibitor YM155-mediated activation of death receptor 5 is crucial for chemotherapy-induced apoptosis in pancreatic carcinoma[J].Mol Cancer Ther,2015,14(1):80-89.
[6] Altieri DC.Survivin,cancer networks and pathway-directed drug discovery[J].Nat Rev Cancer,2008,8(1):61-70.
[7] Santarelli A,Mascitti M,Russo LL,et al.Survivin-based treatment strategies for squamous cell carcinoma[J].Int J Mol Sci,2018,19(4):971.
[8] Xia Q,Chen YL,Zhang RQ,et al.Expressions and clinical significance of Survivin and Anx-A1 in hepatocellular carcinoma[J].Progress in Modern Biomedicine,2016,16(26):5055-5057.[夏芊,陈永亮,张荣强,等.Survivin及Anx-A1在肝癌组织中的表达及其临床意义[J].现代生物医学进展,2016,16(26):5055-5057.]
[9] Zhang R,Ma L,Zheng M,et al.Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice[J].Cancer Gene Ther,2010,17(4):275-288.
[10] Wu C,Gong F,Pang P,et al.An RGD-modified MRI-visible polymeric vector for targeted siRNA delivery to hepatocellular carcinoma in nude mice[J].PLoS One,2013,8(6):e66416.
[11] Ookura M,Fujii T,Yagi H,et al.YM155 exerts potent cytotoxic activity against quiescent (G0/G1) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1[J].Oncotarget,2017,8(67):111535-111550.
[12] Yan X,Su H.YM155 down-regulates Survivin and induces P53 up-regulated modulator of apoptosis (PUMA)-dependent in oral squamous cell carcinoma cells[J].Med Sci Monit,2017,23:1963-1972.
[13] Li WL,Lee MR,Cho MY.The small molecule survivin inhibitor YM155 may be an effective treatment modality for colon cancer through increasing apoptosis[J].Biochem Biophys Res Commun,2016,471(2):309-314.
[14] Dizdar L,Junemann LM,Werner TA,et al.Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer[J].Oncol Lett,2018,15(3):3779-3789.
[15] Chen J,Peng SY,Yun Z,et al.The effect of YM155 on proliferation and apoptosis of osteosarcoma F5M2 cell line[J].Modern Oncology,2017,25(14):2203-2206.[陈洁,彭诗元,贠喆,等.YM155对骨肉瘤细胞系F5M2增殖和凋亡的影响[J].现代肿瘤医学,2017,25(14):2203-2206.]
[16] Hou LJ,Huang XX,Xu LN,et al.YM155 enhances docetaxel efficacy in ovarian cancer[J].Am J Transl Res,2018,10(3):696-708.
[17] Guo WZ,Zhang JK,Wang ZH,et al.Survivin inhibitor YM155 inhibits proliferation of hepatocellular carcinoma cells by inducing autophagy[J].Chinese Journal of Experimental Surgery,2017,34(7):1099-1101.[郭文治,张嘉凯,王智慧,等.生存素抑制剂YM155通过诱导自噬抑制肝癌细胞增殖[J].中华实验外科杂志,2017,34(7):1099-1101.]
[18] Means JC,Venkatesan A,Gerdes B,et al.Drosophila spaghetti and doubletime link the circadian clock and light to caspases,apoptosis and tauopathy[J].PLoS Genet,2015,11(5):e1005171.