Publication
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)
| dc.contributor.author | Coutinho, I. | |
| dc.contributor.author | Pereira, G. | |
| dc.contributor.author | Simoes, M. F. | |
| dc.contributor.author | Corte-Real, M. | |
| dc.contributor.author | Goncalves, J. | |
| dc.contributor.author | Saraiva, L. | |
| dc.date.accessioned | 2015-12-30T10:18:31Z | |
| dc.date.available | 2015-12-30T10:18:31Z | |
| dc.date.issued | 2009 | |
| dc.description.abstract | 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. | |
| dc.format | application/pdf | |
| dc.identifier.citation | BIOCHEMICAL PHARMACOLOGY. - Vol. 78, n. 5 (SEP 1 2009), p. 449-459 | |
| dc.identifier.doi | http://dx.doi.org/10.1016/j.bcp.2009.04.026 | |
| dc.identifier.issn | 0006-2952 | |
| dc.identifier.uri | http://hdl.handle.net/10451/21635 | |
| dc.language.iso | eng | |
| dc.publisher | PERGAMON-ELSEVIER SCIENCE LTD | |
| dc.subject | Pharmacology & Pharmacy | |
| dc.title | 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) | |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.endPage | 459 | por |
| oaire.citation.startPage | 449 | por |
| oaire.citation.title | BIOCHEMICAL PHARMACOLOGY | por |
| oaire.citation.volume | Vol. 78 | por |
| rcaap.rights | restrictedAccess | |
| rcaap.type | article |