6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (
coleon U) is a
diterpene compound isolated from Plectranthus grandidentatus with an antiproliferative effect on several human
cancer cell lines. Herein, we studied the modulatory activity of
coleon U on individual
isoforms of the three
protein kinase C (PKC) subfamilies, classical (cPKC-alpha and -betaI), novel (
nPKC-delta and -epsilon) and atypical (aPKC-zeta), using a yeast PKC assay. The results showed that, whereas the PKC activator phorbol-12-myristate-13-acetate (PMA) activated every PKC tested except aPKC,
coleon U had no effect on aPKC and cPKCs. Besides, the effect of
coleon U on nPKCs was higher than that of PMA. This revealed that
coleon U was a potent and selective activator of nPKCs. The
isoform-selectivity of
coleon U for
nPKC-delta and -epsilon was confirmed using an in vitro PKC assay. Most importantly, while PMA activated nPKCs inducing an
isoform translocation from the cytosol to the plasma membrane and a G2/M cell cycle arrest,
coleon U induced nPKCs translocation to the nucleus and a metacaspase- and mitochondrial-dependent apoptosis. This work therefore reconstitutes in yeast distinct subcellular translocations of a PKC
isoform and the subsequent distinct cellular responses reported for mammalian cells. Together, our study identifies a new
isoform-selective PKC activator with promising pharmacological applications. Indeed, since
coleon U has no effect on cPKCs and aPKC, recognised as
anti-apoptotic proteins, and selectively induces an apoptotic pathway dependent on
nPKC-delta and -epsilon activation, it represents a promising compound for evaluation as an anti-
cancer drug.