1 research outputs found
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