Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21635
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)
Autor: Coutinho, I.
Pereira, G.
Simoes, M. F.
Corte-Real, M.
Goncalves, J.
Saraiva, L.
Palavras-chave: Pharmacology & Pharmacy
Data: 2009
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.
URI: http://hdl.handle.net/10451/21635
DOI: http://dx.doi.org/10.1016/j.bcp.2009.04.026
ISSN: 0006-2952
Aparece nas colecções:FF - Produção Científica 2000-2009

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