CDK7抑制剂THZ1对乳腺癌细胞增殖与凋亡的作用及其机制  

Effect of CDK7 Inhibitor THZ1 on Proliferation and Apoptosis of Breast Cancer Cells and Related Mechanism

作　　者：周燕[1] 刘巧[1] 安盼盼 王红胜[1] 

机构地区：[1]中山大学药学院微生物与生化药学实验室,广州510006

出　　处：《肿瘤防治研究》2017年第6期371-376,共6页Cancer Research on Prevention and Treatment

基　　金：国家自然科学基金(81472470);广东省自然科学基金(c140500000043)

摘　　要：目的探讨细胞周期蛋白依赖性蛋白激酶7(CDK7)特异性抑制剂THZ1对人乳腺癌细胞系MCF7、Sk Br3及Hs578T增殖及凋亡的作用及其分子机制。方法采用MTT、流式细胞术、Western blot等方法检测细胞活力、细胞周期和凋亡的变化情况。结果 500 nmol/L THZ1处理细胞,显微镜观察细胞数明显减少;MTT实验表明THZ1呈剂量及时间依赖性抑制细胞的增殖;细胞饥饿培养24 h以同步化在G1/S期,THZ1继续处理24 h,流式细胞术检测G2/M期细胞数增多。THZ1引起细胞G2/M期阻滞;THZ1呈剂量及时间依赖性诱导细胞早期凋亡与晚期凋亡;Western blot结果表明,THZ1可导致Cleaved-PARP上调,Bcl-2的显著下调和p65、GSK3蛋白磷酸化水平的明显上调。结论 THZ1能抑制MCF7、Sk Br3及Hs578T细胞增殖,诱导其细胞周期阻滞及细胞早、晚期凋亡,可作为乳腺癌治疗潜在的候选药物。Objective To investigate the effect of THZ1, a selective inhibitor of cyclin-dependent protein kinase 7（CDK7）, on the proliferation and apoptosis of human breast cancer cell lines MCF7, SkBr3 and Hs578T. Methods MTT, flow cytometry and Western blot were used in the experiment to detect cell viability, cell cycle and apoptosis. Results After treated with 500 nmol/L THZI, the number of cells was obviously decreased based on microscope observation. MTT assay showed that the proliferation of breast cancer cells was inhibited in a dose- and time-dependent manner after THZ1 treatment. Cells were synchronized at the G1/S transition by starved for 24h, and then treated with indicated doses of THZ 1 for 24h. FCM results showed that the number of cells in G2/M phase was increased, indicating the GJM phase cell cycle arrest was induced. Furthermore, THZ1 induced cells apoptosis in a dose- and time-dependent manner. The expression of Cleaved-PARP were significantly up-regulated and anti-apoptotic gene Bcl-2 were down- regulated, and the NF-κB and GSK3β pathway were activated via increasing the phosphorylation of p65 and GSK3β Conclusion THZ1 can inhibit the proliferation of MCF7, SkBr3 and Hs578T cells, induce cell cycle arrest and cell apoptosis in a dose- and time-dependent manner. It suggested that THZ1 can be used as a potential candidate drug for breast cancer.

关 键 词：CDK7 乳腺癌 凋亡 PARP 

分 类 号：R737.9[医药卫生—肿瘤]