Utilize este identificador para referenciar este registo:
|Título:||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)|
Simoes, M. F.
|Palavras-chave:||Pharmacology & Pharmacy|
|Editora:||PERGAMON-ELSEVIER SCIENCE LTD|
|Citação:||BIOCHEMICAL PHARMACOLOGY. - Vol. 78, n. 5 (SEP 1 2009), p. 449-459|
|Resumo:||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. (C) 2009 Elsevier Inc. All rights reserved.|
|Aparece nas colecções:||FF - Produção Científica 2000-2009|
Ficheiros deste registo:
Não existem ficheiros associados a este registo.