Tubulin-binding agents down-regulate matrix metalloproteinase-2 and -9 in human hormone-refractory prostate cancer cells - A critical role of Cdk1 in mitotic entry
Journal
Biochemical Pharmacology
Journal Volume
94
Journal Issue
1
Pages
12-21
Date Issued
2015
Author(s)
Abstract
Tubulin is an important target for anticancer therapy. Taxanes and vinca alkaloids are two groups of tubulin-binding agents in cancer chemotherapy. Besides tubulin binding, these groups of agents can also down-regulate protein levels of matrix metalloproteinase (MMP)-2 and -9, two important cancer-associated zinc-dependent endopeptidases in invasion and metastasis. However, the mechanism of action waits to be explored. In this study, protein levels but not mRNA expressions of MMP-2 and -9 were down-regulated by paclitaxel (a microtubule-stabilization agent), vincristine and evodiamine (two tubulin-depolymerization agents). These agents induced an increase of protein expression of cyclin B1, MPM2 (mitosis-specific phosphoprotein) and polo-like kinase (PLK) 1 phosphorylation. The data showed a negative relationship between the levels of mitotic proteins and MMP-2 and -9 expressions. MG132 (a specific cell-permeable proteasome inhibitor) blocked mitotic entry and arrested cell cycle at G2 phase, preventing down-regulation of MMP-2 and -9. Cell cycle synchronization experiments by thymidine block or nocodazole treatment showed that mitotic exit inhibited the down-regulation of MMP-2 and -9, confirming negative relationship between cell mitosis and protein levels of MMP-2 and -9 expressions. Cyclin-dependent kinase (Cdk) 1 is a key kinase in mitotic entry. Knockdown of Cdk1 almost completely inhibited the down-regulation of MMP-2 and -9 induced by tubulin-binding agents. In conclusion, the data suggest that mitotic entry and Cdk1 plays a central role in down-regulation of MMP-2 and -9 protein expressions. Tubulin-binding agents cause mitotic arrest and Cdk1 activation, which may contribute largely to the down-regulation of both MMP-2 and -9 expressions. ? 2015 Elsevier Inc. All rights reserved.
Subjects
Cdk1; Matrix metalloproteinase; Mitotic entry and exit; Synchronization; Tubulin-binding agent
SDGs
Other Subjects
benzyloxycarbonylleucylleucylleucinal; cyclin B1; cyclin dependent kinase 1; evodiamine; gelatinase A; gelatinase B; messenger RNA; MPM2 protein; nocodazole; paclitaxel; polo like kinase 1; protein; thymidine; unclassified drug; vincristine; antineoplastic agent; benzyloxycarbonylleucyl-leucyl-leucine aldehyde; CDK1 protein, human; cell cycle protein; cyclin B1; cyclin dependent kinase; evodiamine; gelatinase A; gelatinase B; leupeptin; nocodazole; oncoprotein; paclitaxel; polo-like kinase 1; protein serine threonine kinase; quinazoline derivative; small interfering RNA; tubulin modulator; vincristine; Article; castration resistant prostate cancer; cell cycle arrest; cell cycle G2 phase; cell synchronization; concentration (parameters); controlled study; down regulation; enzyme activation; gene silencing; human; human cell; male; mitosis; mitosis inhibition; priority journal; protein expression; protein function; protein phosphorylation; agonists; antagonists and inhibitors; apoptosis; drug effects; drug resistance; G2 phase cell cycle checkpoint; gene expression regulation; genetics; metabolism; mitosis; signal transduction; tumor cell line; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cyclin B1; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Leupeptins; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitosis; Nocodazole; Paclitaxel; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Quinazolines; RNA, Small Interfering; Signal Transduction; Tubulin Modulators; Vincristine
Type
journal article