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Cisplatin-induced apoptosis in Hep3B cells: Mitochondria-dependent and -independent pathways

 Ji Su Kim  ;  Jae Myun Lee  ;  Yong-Joon Chwae  ;  Yeon Hyang Kim  ;  Jung Hwan Lee  ;  Kunhong Kim  ;  Tae Ho Lee  ;  Se Jong Kim  ;  Jeon Han Park 
 BIOCHEMICAL PHARMACOLOGY, Vol.67(8) : 1459-1468, 2004 
Journal Title
Issue Date
Antineoplastic Agents/pharmacology* ; Apoptosis* ; Biological Transport ; Carrier Proteins/metabolism ; Caspases/metabolism ; Cisplatin/pharmacology* ; Cytochromes c/metabolism ; DNA-Binding Proteins/metabolism ; Down-Regulation ; Genes, Tumor Suppressor ; Humans ; Intracellular Signaling Peptides and Proteins ; Mitochondria/drug effects* ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; NF-kappa B/metabolism ; Nuclear Proteins/metabolism ; Proteins/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2* ; Tumor Cells, Cultured ; Tumor Protein p73 ; Tumor Suppressor Proteins ; X-Linked Inhibitor of Apoptosis Protein ; bcl-2-Associated X Protein
Cisplatin ; Mitochondria ; NF-κB ; p73 ; Hep3B
Human hepatoma cell lines undergo apoptosis after treatment with cisplatin (CP), by mechanisms that are not fully understood, although our previous study demonstrated that Fas-dependent or -independent pathways are involved. To elucidate the mechanisms of CP-induced apoptosis in Hep3B cells, which are Fas- and p53-negative, we investigated mitochondria associated pathways, the involvement of NF-κB, and p73 activation. Results of Western blot and flow cytometry assay revealed that the translocation of Bax, resulted in the loss of mitochondrial membrane potential (Δϕm) and the efflux of cytochrome c and of second mitochondria-derived activator of caspase/DIABLO from mitochondria into the cytosol. Caspase-3, -8 and -9 were activated by CP treatment, however, CP-induced apoptosis was not completely blocked by pretreating with the pan-caspase inhibitor, benzyloxycarbonyl-valinyl-alaninyl-aspartyl-(O-methyl)-fluoromethylketone, indicating that caspase-independent apoptotic pathways might also be involved. RNase protection assay confirmed that NF-κB downregulation leading to the suppression of its target genes, such as XIAP and TRAF2, and p73 accumulation were also observed in Hep3B cells treated with CP. CP-induced apoptosis was inhibited to some extent by transiently overexpressed p73 dominant negative and XIAP, but not by p73DN or XIAP alone. In conclusion, this study demonstrates that CP-induced apoptosis in Hep3B cells is associated with mitochondrial dysregulation, NF-κB downregulation and p73 accumulation.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kun Hong(김건홍) ORCID logo https://orcid.org/0000-0001-5639-6372
Kim, Se Jong(김세종)
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
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