title: Rotundarpene prevents TRAIL-induced apoptosis in human keratinocytes by suppressing the caspase-8- and Bid-pathways and the mitochondrial pathway.
abstract: The extract and hemiterpene glycosides of Ilex rotunda Thunb have demonstrated antioxidant and anti-inflammatory effects. Nevertheless, the effect of rotundarpene on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of rotundarpene on TRAIL-induced apoptosis in human keratinocytes. TRAIL triggers apoptosis by inducing a decrease in the cytosolic levels of Bid, Bcl-2, Bcl-xL, and survivin proteins, increase in the cytosolic levels of Bax, and increase in the mitochondrial levels of VDAC1, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9, and -3), cleavage of PARP-1, and an increase in the tumor suppressor p53 levels. Treatment with rotundarpene prevented TRAIL-induced changes in the levels of apoptosis-related proteins, formations of reactive oxygen species and nitric oxide, nuclear damage, and cell death. These results suggest that rotundarpene may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8- and Bid-pathways and the mitochondria-mediated cell death pathway, which is associated with the formation of reactive oxygen species and reactive nitrogen species. These data suggest that rotundarpene appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.
authors.affiliation: Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea.
authors.forename: Da Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Nam
authors.forename: Yun Jeong
authors.initials: YJ
authors.lastname: Kim
authors.forename: Min Won
authors.initials: MW
authors.lastname: Lee
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002109:Caffeic Acids / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D045782:Hemiterpenes / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D002109:Caffeic Acids; D045782:Hemiterpenes; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C000591680:rotundarpene; D053181:Caspase 8