title: Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis.
abstract: Mitochondrion is one of the master players in both apoptosis and necrosis. We studied the role of mitochondrial function in TRAIL-induced apoptosis. TRAIL killed SK-Hep1 cells with characteristic features of apoptosis such as DNA fragmentation, sub-G1 ploidy peak and cytochrome c translocation. In contrast, mitochondrial DNA-deficient SK-Hep1 rho(0) cells were resistant to TRAIL. Dissipation of mitochondrial potential or cytochrome c translocation did not occur in rho(0) cells after TRAIL treatment. TRAIL induced translocation of Bax subsequent to the cleavage of Bid in parental cells. However, Bax translocation was absent in rho(0) cells, accounting for the failure of cytochrome c release in rho(0) cells. Forced expression of Bax induced caspase-3 activity in rho(0) cells. Incubation of rho(0) cells with ADP+Pi to increase intracellular ATP restored sensitivity to TRAIL. Despite different sensitivity to TRAIL, parental cells and rho(0) cells did not show significant difference in susceptibility to agonistic anti-Fas antibody, TNF-alpha or staurosporine. Our results indicate that TRAIL-induced apoptosis is dependent on intact mitochondrial function and susceptibility of mitochondrial DNA-deficient cells to apoptosis depends on the type of apoptotic stimuli. Tumor cells with mitochondrial mutations or dysfunction might have the ability to evade tumor surveillance imposed by TRAIL in vivo.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea.
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
authors.forename: Byung-Ha
authors.initials: BH
authors.lastname: Oh
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Yong Keun
authors.initials: YK
authors.lastname: Jung
authors.forename: Young Joon
authors.initials: YJ
authors.lastname: Oh
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D004790:Enzyme Induction; D004996:Ethidium / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000648:ultrastructure; D008113:Liver Neoplasms / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D051028:bcl-2-Associated X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004272:DNA, Mitochondrial; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D000255:Adenosine Triphosphate; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D004996:Ethidium