title: Iejimalide C is a potent V-ATPase inhibitor, and induces actin disorganization.
abstract: Iejimalides (IEJLs) A-D are 24-membered macrolides isolated from a tunicate Eudistoma cf. rigida, and exhibit potent cytotoxicity in vitro and antitumor activity in vivo. We previously reported that the molecular target of IEJL-A and -B was the vacuolar-type H(+)-ATPases (V-ATPases). However IEJL-C and -D, which are sulfonylated IEJL-A and -B, respectively, show more potent antitumor activity, and their molecular targets remain to be discovered. Here, we report that IEJL-C is also a potent V-ATPase inhibitor by binding in a site similar to the bafilomycin-binding site. Two-hour treatment with IEJL-C resulted in the complete disappearance of acidic organelles in HeLa cells. Interestingly, after 24-h treatment, small actin aggregates were observed instead of actin fibers. The same actin reorganization was also observed in cells treated with another V-ATPase inhibitor, bafilomycin A1. Because IEJLs did not inhibit actin polymerization in vitro, these results suggest that the primary target of IEJL-C, as well as IEJL-A and -B, is V-ATPase, and actin reorganizations are probably caused by the disruption of pH homeostasis via V-ATPase inhibition.
authors.affiliation: Tsukuba Research Laboratory, Hamamatsu Photonics K.K.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kazami
authors.forename: Masak
authors.initials: M
authors.lastname: Takaine
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Itoh
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kubota
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
mesh_terms: D000199:Actins / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D015003:Yeasts
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D002219:Carbamates; D018942:Macrolides; C520299:iejimalide C; D025262:Vacuolar Proton-Translocating ATPases