Dynasore, a dynamin inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments.
Dynamic remodeling of actin filaments are bases for a variety of cellular events including cell motility and cancer invasion, and the regulation of actin dynamics implies dynamin, well characterized endocytotic protein. Here we report that dynasore, a inhibitor of dynamin GTPase, potently destabilizes F-actin in vitro, and it severely inhibits the formation of pseudopodia and cancer cell invasion, both of which are supported by active F-actin formation. Dynasore rapidly disrupted F-actin formed in brain cytosol in vitro, and the dynasore's effect on F-actin was indirect. Dynasore significantly suppressed serum-induced lamellipodia formation in U2OS cell. Dynasore also destabilized F-actin in resting cells, which caused the retraction of the plasma membrane. A certain amount of dynamin 2 in U2OS cells localized along F-actin, and co-localized with cortactin, a physiological binding partner of dynamin and F-actin. However, these associations of dynamin were partially disrupted by dynasore treatment. Furthermore, invasion activity of H1080 cell, a lung cancer cell line, was suppressed by approximately 40% with dynasore treatment. These results strongly suggest that dynasore potently destabilizes F-actin, and the effect implies dynamin. Dynasore or its derivative would be suitable candidates as potent anti-cancer drugs.
Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-Cho, Kita-ku, Okayama 700-8558, Japan.
Hiroshi
H
Yamada
Tadashi
T
Abe
Shun-Ai
SA
Li
Yuki
Y
Masuoka
Mihoko
M
Isoda
Masami
M
Watanabe
Yasutomo
Y
Nasu
Hiromi
H
Kumon
Akira
A
Asai
Kohji
K
Takei
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051356:Cortactin / Q000378:metabolism; D034285:Dynamin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011554:Pseudopodia / Q000187:drug effects* / Q000502:physiology
D000970:Antineoplastic Agents; D051356:Cortactin; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D034285:Dynamin II