Selective activation of protein kinase C-delta and -epsilon by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U).

Abstract

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.

• Authors: I Coutinho, G Pereira, M F Simões, M Côrte-Real, J Gonçalves, L Saraiva
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 78 Issue 5 Pg. 449-59 (Sep 01 2009) ISSN: 1873-2968 [Electronic] England
• PMID: 19413996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diterpenes
• Enzyme Activators
• coleon U
• Protein Kinase C-delta
• Protein Kinase C-epsilon

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Diterpenes (pharmacology)
• Enzyme Activation
• Enzyme Activators (pharmacology)
• Protein Kinase C-delta (metabolism)
• Protein Kinase C-epsilon (metabolism)
• Rats
• Saccharomyces cerevisiae (cytology, drug effects)