title: 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.
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.
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan; The Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Chang
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Yu
authors.affiliation: The Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: chen.844@osu.edu.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: School of Pharmacy, National Taiwan University, No. 1, Sect. 1, Jen-Ai Rd, Taipei 100, Taiwan. Electronic address: jhguh@ntu.edu.tw.
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050257:Tubulin Modulators / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D018844:Cyclin-Dependent Kinases; D007976:Leupeptins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015739:Nocodazole; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; D014750:Vincristine; D000097869:Polo-Like Kinase 1; C049639:evodiamine; C528899:CDK1 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Cdk1; Matrix metalloproteinase; Mitotic entry and exit; Synchronization; Tubulin-binding agent