Aurora-A促进鼻咽癌化疗抵抗的机制研究
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摘要
目的探讨丝/苏氨酸蛋白激酶Aurora-A促进鼻咽癌化疗抵抗的机制。方法应用Western blot和Q-PCR检测鼻咽癌组织及癌旁正常组织中Aurora-A的表达水平。选取Aurora-A高表达的鼻咽癌细胞系CNE2,添加Aurora-A激酶抑制剂60nmVX680处理8小时后,加入浓度为10μg/ml的顺铂处理24小时,收集细胞通过流式细胞术检测细胞凋亡情况,同时WB和Q-PCR检测细胞凋亡相关信号通路蛋白的表达情况。结果 Aurora-A在鼻咽癌组织中表达水平明显高于癌旁正常组织,相对于正常鼻咽细胞NP69,Aurora-A在不同鼻咽癌细胞中表达显著升高且在CNE2中表达最高;相对于未处理CNE2,添加顺铂或/和Aurora-A抑制剂VX680处理的CNE2细胞能显著促进鼻咽癌细胞凋亡及p-AKT、p21及Cleaved-Caspase-3的表达。结论 Aurora-A通过p-AKT/p21/Cleaved-Caspase-3通路促进鼻咽癌的化疗抵抗。
OBJECTIVE To explore the mechanism of Aurora kinase A(Aurora-A) promoting cancer cell chemotherapy resistance in nasopharyngeal carcinoma. METHODS The expression of Aurora-A in nasopharyngeal carcinoma tissues and adjacent tissues were detected by Western bolt and Q-PCR. The highexpressing Aurora A cell line CNE2 was used to detected the cell apoptosis and the expression of key pathway marker protein after Aurora-A inhibitor VX680 and cisplatin treatment by using Flow cytometry and WB. RESULTS The expression of Aurora-A in nasopharyngeal carcinoma tissues was significantly higher than that in adjacent tissues.Comparing to normal nasopharyngeal cells NP69, Aurora-A was significantly highly expressed in all of nasopharyngeal carcinoma cells and was highest in CNE2. Inhibiton of Aurora-A increased the cell apoptosis and the expression of p-AKT, p21 and Cleaved-Caspase-3 after using cisplatin or the Aurora-A inhibitor VX680 treatment. CONCLUSION The results shown that Aurora-A confer chemoresistance to cisplatin treatment through p-AKT/p21/Cleaved-Caspase-3 pathway.
OBJECTIVE To explore the mechanism of Aurora kinase A(Aurora-A) promoting cancer cell chemotherapy resistance in nasopharyngeal carcinoma. METHODS The expression of Aurora-A in nasopharyngeal carcinoma tissues and adjacent tissues were detected by Western bolt and Q-PCR. The highexpressing Aurora A cell line CNE2 was used to detected the cell apoptosis and the expression of key pathway marker protein after Aurora-A inhibitor VX680 and cisplatin treatment by using Flow cytometry and WB. RESULTS The expression of Aurora-A in nasopharyngeal carcinoma tissues was significantly higher than that in adjacent tissues.Comparing to normal nasopharyngeal cells NP69, Aurora-A was significantly highly expressed in all of nasopharyngeal carcinoma cells and was highest in CNE2. Inhibiton of Aurora-A increased the cell apoptosis and the expression of p-AKT, p21 and Cleaved-Caspase-3 after using cisplatin or the Aurora-A inhibitor VX680 treatment. CONCLUSION The results shown that Aurora-A confer chemoresistance to cisplatin treatment through p-AKT/p21/Cleaved-Caspase-3 pathway.
引文
[1]Wang LH,Xiang J,Yan M,et al.The mitotic kinase Aurora-Ainduces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway.Cancer Res,2010,70(22):9118-9128.
[2]Long M,Yin G,Liu L,et al.Adenovirus-mediated Aurora AshRNA driven by stathmin promoter suppressed tumor growth and enhanced paclitaxel chemotherapy sensitivity in human breast carcinoma cells.Cancer Gene,2012,19(4):271-281.
[3]Xie Y,Zhu S,Zhong M,et al.Inhibition of Aurora Kinase AInduces Necroptosis in Pancreatic Carcinoma.Gastroenterology,2017,153(5):1429-1443.
[4]Meraldi P,Honda R,Nigg EA.Aurora kinases link chromosome segregation and cell division to cancer susceptibility.Cur Opinion Gen Dev,2004,14(1):29-36.
[5]Sun JM,Yang LN,Xu H,et al.Inhibition of Aurora A promotes chemosensitivity via inducing cell cycle arrest and apoptosis in cervical cancer cells.Am J Cancer Res,2015,5(3):1133-1145.
[6]Schmitt E,Boutros R,Froment C,et al.CHK1 phosphorylates CDC25B during the cell cycle in the absence of DNA damage.JCS,2006,119(20):4269-4275.
[7]Opyrchal M,Gil M,Salisbury JL,et al.Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells.Oncotarget,2017,8(53):91803-91816.
[8]Tanaka E,Hashimoto Y,Ito T,et al.The suppression of aurora-A/STK15/BTAK expression enhances chemosensitivity to docetaxel in human esophageal squamous cell carcinoma.Cancer Res,2007,13(4):1331-1340.
[9]Tian H,Gao Z,Li H,et al.DNA damage response--a doubleedged sword in cancer prevention and cancer therapy.Cancer Let,2015,358(1):8-16.
[10]Sun H,Wang Y,Wang Z,et al.Aurora-A controls cancer cell radio-and chemoresistance via ATM/Chk2-mediated DNA repair networks.Bio Acta,2014,1843(5):934-944.
[11]Ke CS,Liu HS,Yen CH,et al.Curcumin-induced Aurora-Asuppression not only causes mitotic defect and cell cycle arrest but also alters chemosensitivity to anticancer drugs.J Nutrit Bio,2014,25(5):526-539.
[12]Gilardini Montani MS,D'Eliseo D,Cirone M,et al.Capsaicinmediated apoptosis of human bladder cancer cells activates dendritic cells via CD91.Nutrition,2015,31(4):578-581.
[2]Long M,Yin G,Liu L,et al.Adenovirus-mediated Aurora AshRNA driven by stathmin promoter suppressed tumor growth and enhanced paclitaxel chemotherapy sensitivity in human breast carcinoma cells.Cancer Gene,2012,19(4):271-281.
[3]Xie Y,Zhu S,Zhong M,et al.Inhibition of Aurora Kinase AInduces Necroptosis in Pancreatic Carcinoma.Gastroenterology,2017,153(5):1429-1443.
[4]Meraldi P,Honda R,Nigg EA.Aurora kinases link chromosome segregation and cell division to cancer susceptibility.Cur Opinion Gen Dev,2004,14(1):29-36.
[5]Sun JM,Yang LN,Xu H,et al.Inhibition of Aurora A promotes chemosensitivity via inducing cell cycle arrest and apoptosis in cervical cancer cells.Am J Cancer Res,2015,5(3):1133-1145.
[6]Schmitt E,Boutros R,Froment C,et al.CHK1 phosphorylates CDC25B during the cell cycle in the absence of DNA damage.JCS,2006,119(20):4269-4275.
[7]Opyrchal M,Gil M,Salisbury JL,et al.Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells.Oncotarget,2017,8(53):91803-91816.
[8]Tanaka E,Hashimoto Y,Ito T,et al.The suppression of aurora-A/STK15/BTAK expression enhances chemosensitivity to docetaxel in human esophageal squamous cell carcinoma.Cancer Res,2007,13(4):1331-1340.
[9]Tian H,Gao Z,Li H,et al.DNA damage response--a doubleedged sword in cancer prevention and cancer therapy.Cancer Let,2015,358(1):8-16.
[10]Sun H,Wang Y,Wang Z,et al.Aurora-A controls cancer cell radio-and chemoresistance via ATM/Chk2-mediated DNA repair networks.Bio Acta,2014,1843(5):934-944.
[11]Ke CS,Liu HS,Yen CH,et al.Curcumin-induced Aurora-Asuppression not only causes mitotic defect and cell cycle arrest but also alters chemosensitivity to anticancer drugs.J Nutrit Bio,2014,25(5):526-539.
[12]Gilardini Montani MS,D'Eliseo D,Cirone M,et al.Capsaicinmediated apoptosis of human bladder cancer cells activates dendritic cells via CD91.Nutrition,2015,31(4):578-581.