Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis

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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 e 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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2002-05
Language
English
Article Type
Article
Keywords

TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; FADD-DEPENDENT APOPTOSIS; CYTOCHROME-C; LIGAND TRAIL; TUMORICIDAL ACTIVITY; CRYSTAL-STRUCTURE; MELANOMA-CELLS; TNF; EXPRESSION

Citation

ONCOGENE, v.21, no.20, pp.3139 - 3148

ISSN
0950-9232
DOI
10.1038/sj.onc.1205406
URI
http://hdl.handle.net/10203/85620
Appears in Collection
BS-Journal Papers(저널논문)
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