Tissue inhibitor of metalloproteinase-1 protects MCF-7 breast cancer cells from paclitaxel-induced apoptosis by decreasing the stability of cyclin B1.
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 G(2)/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.
Wang
Ting
T
Nanjing Medical University, China.
Lv
Jing-Huan
JH
Zhang
Xiong-Fei
XF
Li
Chao-Jun
CJ
Han
Xiao
X
Sun
Yu-Jie
YJ
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D056744:Cyclin B1; D019715:Tissue Inhibitor of Metalloproteinase-1; D017239:Paclitaxel