title: Selective Modulation of Protein Kinase C α over Protein Kinase C ε by Curcumin and Its Derivatives in CHO-K1 Cells.
abstract: Members of the protein kinase C (PKC) family of serine/threonine kinases regulate various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. Modulation of isoform-selective activity of PKC by curcumin (1), the active constituent of Curcuma L., is poorly understood, and the literature data are inconsistent and obscure. The effect of curcumin (1) and its analogues, 4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl oleate (2), (9Z,12Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12-dienoate (3), (9Z,12Z,15Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12,15-trienoate (4), and (1E,6E)-1-[4-(hexadecyloxy)-3-methoxyphenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (5), and didemethylcurcumin (6) on the membrane translocation of PKCα, a conventional PKC, and PKCε, a novel PKC, has been studied in CHO-K1 cells, in which these PKC isoforms are endogenously expressed. Translocation of PKC from the cytosol to the membrane was measured using immunoblotting and confocal microscopy. 1 and 6 inhibited the TPA-induced membrane translocation of PKCα but not of PKCε. Modification of the hydroxyl group of curcumin with a long aliphatic chain containing unsaturated double bonds in 2-4 completely abolished this inhibition property. Instead, 2-4 showed significant translocation of PKCα but not of PKCε to the membrane. No membrane translocation was observed with 1, 6, or the analogue 5 having a saturated long chain for either PKCα or PKCε. 1 and 6 inhibited TPA-induced activation of ERK1/2, and 2-4 activated it. ERK1/2 is the downstream readout of PKC. These results show that the hydroxyl group of curcumin is important for PKC activity and the curcumin template can be useful in developing isoform specific PKC modulators for regulating a particular disease state.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States.
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Pany
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States.
authors.forename: Anjoy
authors.initials: A
authors.lastname: Majhi
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Houston, Texas 77204, United States.
authors.forename: Joydip
authors.initials: J
authors.lastname: Das
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D003474:Curcumin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007700:Kinetics; D054878:Lipoylation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008745:Methylation; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D003474:Curcumin