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)

• Type: Article in International Scientific Journal
• Date: 2009

Authors

Coutinho, I (Author) Other; Pereira, G (Author) Other; Simoes, MF (Author) Other; Corte Real, M (Author) Other; Goncalves, J (Author) FFUP; Saraiva, L (Author) FFUP

Journal

Title: Biochemical Pharmacology

Vol. 78 No. 5

Pages: 449-459

ISSN: 0006-2952

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 15 Citations

Scopus - 15 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-003-FXQ

DOI: 10.1016/j.bcp.2009.04.026

Abstract (EN): 6,11,1 2,14-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 -beta 1), 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11