JASPLAKINOLIDE, A CYTOTOXIC NATURAL PRODUCT, INDUCES ACTIN POLYMERIZATION AND COMPETITIVELY INHIBITS THE BINDING OF PHALLOIDIN TO F-ACTIN

Jasplakinolide, a naturally occurring cyclic peptide from the marine s ponge, Jaspis johnstoni, has both fungicidal and antiproliferative act ivity. We now report that this peptide is a potent inducer of actin po lymerization in vitro. The peptide has a much greater effect on Mg2+-a ctin than on Ca2+-actin. Competitive binding studies using rhodamine-p halloidin suggest that jasplakinolide binds to F-actin competitively w ith phalloidin with a dissociation constant of approximately 15 nM. Th is compares favorably to the previously reported IC50 of 35 nn for the antiproliferative effect of jasplakinolide on PC3 prostate carcinoma cells. The binding curve suggests that nearest neighbor positive coope rativity influences the binding of jasplakinolide (and perhaps also ph alloidin) to F actin. These results imply that jasplakinolide may exer t its cytotoxic effect in vivo by inducing actin polymerization and/or stabilizing pre-existing actin filaments.