title: Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCalpha.
abstract: Phorbol esters, the archetypical (PKC) activators, induce apoptosis in androgen-sensitive LNCaP prostate cancer cells. In this study we evaluate the effect of a novel class of PKC ligands, the diacylglycerol (DAG)-lactones, as inducers of apoptosis in LNCaP cells. These unique ligands were designed using novel pharmacophore- and receptor-guided approaches to achieve highly potent DAG surrogates. Two of these compounds, HK434 and HK654, induced apoptosis in LNCaP cells with much higher potency than oleoyl-acetyl-glycerol or phorbol 12,13-dibutyrate. Moreover, different PKC isozymes were found to mediate the apoptotic effect of phorbol 12-myristate 13-acetate (PMA) and HK654 in LNCaP cells. Using PKC inhibitors and dominant negative PKC isoforms, we found that both PKCalpha and PKCdelta mediated the apoptotic effect of PMA, whereas only PKCalpha was involved in the effect of the DAG-lactone. The PKCalpha selectivity of HK654 in LNCaP cells contrasts with similar potencies in vitro for binding and activation of PKCalpha and PKCdelta. Consistent with the differences in isoform dependence in intact cells, PMA and HK654 show marked differences in their abilities to translocate PKC isozymes. Both PMA and HK654 induce a marked redistribution of PKCalpha to the plasma membrane. On the other hand, unlike PMA, HK654 translocates PKCdelta predominantly to the nuclear membrane. Thus, DAG-lactones have a unique profile of activation of PKC isozymes for inducing apoptosis in LNCaP cells and represent the first example of a selective activator of a classical PKC in cellular models. An attractive hypothesis is that selective activation of PKC isozymes by pharmacological agents in cells can be achieved by differential intracellular targeting of each PKC.
authors.affiliation: Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Garcia-Bermejo
authors.forename: Federico Coluccio
authors.initials: FC
authors.lastname: Leskow
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Fujii
authors.forename: Qiming
authors.initials: Q
authors.lastname: Wang
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Motoi
authors.initials: M
authors.lastname: Ohba
authors.forename: Toshio
authors.initials: T
authors.lastname: Kuroki
authors.forename: Kee-Chung
authors.initials: KC
authors.lastname: Han
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Kazanietz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004075:Diglycerides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011493:Protein Kinase C / Q000032:analysis / Q000037:antagonists & inhibitors / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004075:Diglycerides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007783:Lactones; D019253:Proto-Oncogene Proteins c-bcl-2; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate