title: Characterization of 4-O-methyl-ascochlorin-induced apoptosis in comparison with typical apoptotic inducers in human leukemia cell lines.
abstract: Apoptosis can be induced by various stimuli such as the ligands of death receptors, chemotherapeutic drugs and irradiation. It is generally believed that chemotherapeutic drugs induce mitochondrial damage, cytochrome c release and activation of caspase-9, leading to apoptosis. Here, we found that an isoprenoid antibiotic, 4-O-methyl ascochlorin, significantly induces typical apoptotic events in Jurkat cells including the degradation of poly (ADP-ribose) polymerase, DNA fragmentation, activation of caspase-3, -9 and -8, and cytochrome c release from mitochondria. Similar to Fas stimulation, 4-O-methyl ascochlorin but not staurosporine, cycloheximide and actinomycin D, induced apoptosis in SKW6.4 cells, in which apoptosis is strongly dependent on death-inducing signaling-complex. Bcl-2 overexpression in Jurkat cells completely suppressed the apoptosis, but procaspase-9 processing was partially induced. A caspase-8 inhibitor, IETD-fmk, effectively suppressed poly (ADP-ribose) polymerase cleavage and cytochrome c release. However, 4-O-methyl ascochlorin induced apoptosis in Jurkat cells deficient of caspase-8 or Fas-associated death domain protein. These results suggest that 4-O-methyl ascochlorin induces apoptosis through the mechanism distinct from conventional apoptosis inducers.
authors.affiliation: Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa, Chiba 277-0861, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuruga
authors.forename: H
authors.initials: H
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Ozawa
authors.forename: M
authors.initials: M
authors.lastname: Togashi
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chang
authors.forename: K
authors.initials: K
authors.lastname: Ando
authors.forename: J
authors.initials: J
authors.lastname: Magae
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D019169:Jurkat Cells; D009842:Oligopeptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D061945:Caspase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007075:Immunoglobulin M; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D013729:Terpenes; D019014:fas Receptor; C425644:isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D003609:Dactinomycin; C031515:4-O-methylascochlorin; D045304:Cytochromes c; D003513:Cycloheximide; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine