title: Bufalin prevents the migration and invasion of T24 bladder carcinoma             cells through the inactivation of matrix metalloproteinases and modulation of             tight junctions.
abstract: Bufalin, a cardiotonic steroid extracted from toad venom, has generally             been known to possess a range of biological activities; however, only a few studies             have reported the anti-metastatic activity of bufalin. In the present study, we             investigated the inhibitory effects of bufalin on cell migration and invasion,             two critical cellular processes that are often deregulated during metastasis,             using the human bladder cancer cell line, T24. Within the concentration range             that was not cytotoxic, bufalin markedly inhibited the cell motility and invasiveness             of T24 cells. The inhibitory effects of bufalin on cell invasiveness were associated             with the tightening of tight junctions (TJs), which was demonstrated by an increase             in transepithelial electrical resistance (TER). Bufalin treatment also repressed             the levels of claudin proteins (claudin-2, -3 and -4) and the major components             of TJs that play key roles in the control and selectivity of paracellular transport.             Furthermore, the activities of matrix metalloproteinase (MMP)‑2 and -9 in T24             cells were dose‑dependently inhibited by treatment with bufalin and this also             correlated with a decrease in their mRNA and protein expression levels; however,             the mRNA and protein levels of the tissue inhibitor of metalloproteinase (TIMP)‑1             and -2 were increased. In addition, these effects were related to the increased             phosphorylation of the extracellular signal-regulated protein kinase (ERK) pathway.             The inhibition of ERK (PD98059) significantly prevented the bufalin‑induced suppression             of T24 cell migration. These findings suggest that bufalin inhibits the migration             and invasion of T24 cells by modulating the activity of TJs and MMPs, possibly             in association with the activation of ERK.
authors.affiliation: Department of Biochemistry and Research Institute of Oriental Medicine, Dongeui University College of Oriental Medicine, Busan, Republic of Korea.
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002018:Bufanolides / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D017097:Electric Impedance; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases; D000254:Sodium-Potassium-Exchanging ATPase; C022777:bufalin