Inhibition of microtubule assembly by a complex of actin and antitumor macrolide aplyronine A.
Aplyronine A (ApA) is a marine natural product that shows potent antitumor activity. While both ApA and ApC, a derivative of ApA that lacks a trimethylserine ester moiety, inhibit actin polymerization in vitro to the same extent, only ApA shows potent cytotoxicity. Therefore, the molecular targets and mechanisms of action of ApA in cells have remained unclear. We report that ApA inhibits tubulin polymerization in a hitherto unprecedented way. ApA forms a 1:1:1 heterotrimeric complex with actin and tubulin, in association with actin synergistically binding to tubulin, and inhibits tubulin polymerization. Tubulin-targeting agents have been widely used in cancer chemotherapy, but there are no previous descriptions of microtubule inhibitors that also bind to actin and affect microtubule assembly. ApA inhibits spindle formation and mitosis in HeLa S3 cells at 100 pM, a much lower concentration than is needed for the disassembly of the actin cytoskeleton. The results of the present study indicate that ApA represents a rare type of natural product, which binds to two different cytoplasmic proteins to exert highly potent biological activities.
Graduate School of Pure and Applied Sciences and ‡Graduate School of Life and Environmental Sciences, University of Tsukuba , 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
Masaki
M
Kita
Yuichiro
Y
Hirayama
Kozo
K
Yoneda
Kota
K
Yamagishi
Takumi
T
Chinen
Takeo
T
Usui
Eriko
E
Sumiya
Motonari
M
Uesugi
Hideo
H
Kigoshi
D000199:Actins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D001688:Biological Products; D018942:Macrolides; D014404:Tubulin; C104057:aplyronine A