Tissue inhibitor of metalloproteinase‐1 protects MCF‐7 breast cancer cells from paclitaxel‐induced apoptosis by decreasing the stability of cyclin B1
Tissue inhibitor of metalloproteinase‐1 protects MCF‐7 breast cancer cells from paclitaxel‐induced apoptosis by decreasing the stability of cyclin B1
复制标题
DOI：
10.1002/ijc.24753
复制
发表时间：
2010-01
影响因子：
6.4
通讯作者：
Ting Wang;J. Lv;Xiongfei Zhang;Chaojun Li;Xiao Han;Yu-jie Sun
中科院分区：
文献类型：
--
作者：
Ting Wang;J. Lv;Xiongfei Zhang;Chaojun Li;Xiao Han;Yu-jie Sun
紫杉醇（PTX）是治疗肿瘤的有效药物。它干扰微管动力学，损害细胞从有丝分裂中期到后期的过渡，导致细胞凋亡死亡。然而，PTX在癌症化疗中的有效性受到一些患者的耐药性的阻碍。金属蛋白酶组织抑制剂-1（TIMP-1）被认为能够抑制细胞凋亡。肿瘤组织TIMP-1水平升高与化疗反应不良显著相关。我们假设TIMP-1可以通过抑制凋亡来降低乳腺癌细胞对PTX的敏感性。为了验证这一假设，我们首先检查了TIMP-1对PTX诱导的细胞凋亡的影响，并研究了TIMP-1对细胞周期蛋白B1的表达和稳定性的影响，细胞周期蛋白B1在MCF-7乳腺癌细胞有丝分裂期间关键地调节中期到后期的转变。我们的数据表明，TIMP-1可以显著降低MCF-7细胞对PTX诱导的凋亡的敏感性，减弱G2/M期有丝分裂阻滞，并增强cyclin B1的降解。为了进一步研究TIMP-1对PTX诱导的细胞凋亡的抑制作用是否是通过降低细胞周期蛋白B1的水平介导的，将细胞周期蛋白B1表达质粒转染到过表达TIMP-1的克隆中。然后分析PTX诱导的细胞凋亡水平。数据显示，PTX诱导的细胞凋亡中基于TIMP-1的减少被细胞周期蛋白B1逆转。我们的数据表明，TIMP-1可以通过降低细胞周期蛋白B1的稳定性来保护乳腺癌细胞免受PTX诱导的凋亡。
Paclitaxel (PTX) is a very effective drug in treating tumors. It disturbs microtubule dynamics and impairs the transition of cells from metaphase to anaphase in mitosis, leading to cell death by apoptosis. However, the effectiveness of PTX in cancer chemotherapy is hampered by drug resistance in some patients. Tissue inhibitor of metalloproteinase‐1 (TIMP‐1) is well known to be capable of inhibiting apoptosis. Elevated tumor tissue TIMP‐1 levels have been significantly associated with a poor response to chemotherapy. We hypothesized that TIMP‐1 could reduce the sensitivity of breast cancer cells to PTX by inhibiting apoptosis. To test this hypothesis, we first examined the effects of TIMP‐1 on the apoptosis induced by PTX and investigated the effects of TIMP‐1 on the expression and stability of cyclin B1 that critically regulates the metaphase to anaphase transition during mitosis in MCF‐7 breast cancer cells. Our data demonstrate that TIMP‐1 could significantly decrease the sensitivity of MCF‐7 cells to PTX‐induced apoptosis, attenuate mitotic blockage in G2/M, and enhance the degradation of cyclin B1. To further investigate whether the inhibitory effect of TIMP‐1 on PTX‐induced apoptosis is mediated by lowering levels of cyclin B1, a cyclin B1‐expression plasmid was transfected into clone overexpressing TIMP‐1. The levels of PTX‐induced apoptosis were then analyzed. The data showed that the TIMP‐1‐based decrease in PTX‐induced apoptosis was reversed by cyclin B1. Our data indicate that TIMP‐1 can protect breast cancer cells from PTX‐induced apoptosis by decreasing the stability of cyclin B1.