Utilize este identificador para referenciar este registo:
https://hdl.handle.net/1822/51054
Título: | Selective activation of protein kinase C-δ and -ɛ by 6,11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U) |
Autor(es): | Coutinho, Isabel Pereira, G. Simões, M. F. Côrte-Real, Manuela Gonçalves. Jorge Saraiva, L. |
Palavras-chave: | Coleon U Selective PKC activator PKC-delta PKC-epsilon Apoptosis Yeast PKC-δ PKC-ε |
Data: | 2009 |
Editora: | Pergamon-Elsevier Science Ltd |
Revista: | Biochemical Pharmacology |
Resumo(s): | 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-α and -βI), novel (nPKC-δ and -ɛ) and atypical (aPKC-ζ), 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-δ and -ɛ 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-δ and -ɛ activation, it represents a promising compound for evaluation as an anti-cancer drug. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/51054 |
DOI: | 10.1016/j.bcp.2009.04.026 |
ISSN: | 0006-2952 |
Arbitragem científica: | yes |
Acesso: | Acesso aberto |
Aparece nas coleções: | DBio - Artigos/Papers |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Coutinho et al 2015.pdf | 664,08 kB | Adobe PDF | Ver/Abrir |