Vincristine enhances amoeboid-like motility via GEF-H1/RhoA/ROCK/Myosin light chain signaling in MKN45 cells
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概要
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Background: Anti-cancer drugs are widely used in cancer treatment frequently combined with surgical therapyand/or radiation therapy. Although surgery and radiation have been suggested to facilitate invasion and metastasisof tumor cells in some cases, there is so far little information about the effect of anti-cancer drugs on cellularinvasive ability and metastasis. In this study, using four different anti-cancer drugs (vincristine, paclitaxel, cisplatinand etoposide), we examined whether these drugs influence the invasive ability of tumor cells.Methods: Human gastric adenocarcinoma MKN45 cells were used to evaluate the effect of anti-cancer drugs. Afterdrug treatment, cellular invasive ability was assessed using the Matrigel invasion chamber. Cytoskeletal changesafter treatment were examined microscopically with F-actin staining. In addition, we monitored cellular motility in3D matrigel environment by time-lapse microscopic analysis. The drug-induced activation of RhoA and ROCK wasevaluated by pull-down assay and Western blotting using an antibody against phosphorylated myosin light chain(MLC), respectively. Where necessary, a ROCK inhibitor Y27632 and siRNA for guanine nucleotide exchangefactor-H1 (GEF-H1) were applied.Results: Among all drugs tested, only vincristine stimulated the invasive ability of MKN45 cells. Microscopic analysisrevealed that vincristine induced the formation of non-apoptotic membrane blebs and amoeboid-like motility.Vincristine significantly enhanced RhoA activity and MLC phosphorylation, suggesting the involvement of RhoA/ROCK pathway in the vincristine-induced cytoskeletal reorganization and cellular invasion. Furthermore, we foundthat Y27632 as well as the siRNA for GEF-H1, a RhoA-specific activator, attenuated MLC phosphorylation, theformation of membrane blebs and the invasive ability after vincristine treatment.Conclusions: These results indicate that vincristine activates GEF-H1/RhoA/ROCK/MLC signaling, thereby promotingamoeboid-like motility and the invasive ability of MKN45 cells.
著者
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Inanami Osamu
弘前大学 保健学研究科放射線生命科学
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Inanami Osamu
Laboratory Of Radiation Biology Graduate School Of Veterinary Medicine Hokkaido University
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Inanami Osamu
Lab. Radiat. Biol. Grad. Sch. Vet. Med. Hokkaido Univ.
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Yamamori Tohru
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Meike Shunsuke
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Eitaki Masato
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Yamamori Tohru
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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Yasui Hironobu
Laboratory Of Radiation Biology Department Of Environmental Veterinary Sciences Graduate School Of V
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