辛伐他汀通过YAP/TAZ抗前列腺癌细胞增殖的作用及机制研究

Simvastatin inhibits prostate cancer cell growth via suppressing YAP/TAZ activity

目的:考察辛伐他汀对22Rv1和DU145前列腺癌细胞的增殖抑制作用,并对其作用机制进行初步的探讨。方法:复苏并培养22Rv1和DU145前列腺癌细胞株,给予不同浓度辛伐他汀(2μmol/L、10μmol/L、50μmol/L)进行干预。辛伐他汀对22Rv1和DU145前列腺癌细胞的增殖抑制作用采用MTT法检测;对22Rv1和DU145前列腺癌细胞凋亡的影响用流式检测;对22Rv1和DU145前列腺癌细胞增殖相关蛋白p-mTOR(Ser2448)、p-Akt(Ser473)、凋亡相关蛋白Caspase-3、Caspase-9、PARP以及YAP、p-YAP、 TAZ表达的影响用Western Blot检测;通过过表达TAZ考察TAZ在辛伐他汀抗前列腺癌细胞增殖中的作用。结果:辛伐他汀抑制22Rv1和DU145前列腺癌细胞的增殖,并呈浓度依赖性和时间依赖性,在分子水平,辛伐他汀浓度依赖性地抑制了p-mTOR(Ser2448)和p-Akt(Ser473)的表达;辛伐他汀浓度依赖性地诱导22Rv1和DU145前列腺癌细胞发生凋亡,并在分子水平浓度依赖性地促进了Caspase-3、Caspase-9和PARP的剪切;辛伐他汀浓度依赖性地上调p-YAP的表达,抑制TAZ的表达,过表达TAZ减弱了辛伐他汀对前列腺癌细胞的凋亡诱导作用和增殖抑制作用。结论:辛伐他汀可能通过抑制YAP/TAZ诱导前列腺癌细胞凋亡,抑制前列腺癌细胞的增殖。

Objective:To investigate the inhibitory effect of simvastatin on the growth of 22 Rv1 and DU145 prostate cancer cells and its underlying mechanisms.Methods:22 Rv1 and DU145 cells were cultured and treated with simvastatin with different concentrations(2 μmol/L,10 μmol/L,50 μmol/L).The inhibition rate of simvastatin on 22 Rv1 and DU145 cells was detected by MTT.Apoptosis rate was measured by flow cytometry.The effect of simvastatin on the expression of p-mTOR(Ser2448),p-Akt(Ser473),Caspase-3,Caspase-9,PARP,YAP,p-YAP,TAZ was detected by western blot.Overexpression of TAZ was used to investigate the role of TAZ played in simvastatin caused inhibition of cells growth.Results:Simvastatin significantly inhibited cell growth of 22 Rv1 and DU145 cells in a time and dose dependent manner.Simvastatin also suppressed the expression of p-mTOR(Ser2448),p-Akt(Ser473) and promoted the cleavage of Caspase 3,Caspase 9 and PARP.Simvastatin also promoted the expression of p-YAP and down-regulated the expression of TAZ.Overexpression of TAZ attenuated the inhibitory effect of simvastatin on cell growth in both 22 Rv1 and DU145 cells.Conclusion:Simvastatin induces apoptosis and inhibits the proliferation of prostate cancer cells possibly via suppressing YAP/TAZ activity.