title: The time-dependent serial gene response to Zeocin treatment involves caspase-dependent apoptosis in HeLa cells.
abstract: Zeocin, a member of the bleomycin/phleomycin family of antibiotics, is known to bind DNA and to induce apoptosis in cervical cancer cells, but the mechanism underlying this apoptotic response is poorly understood. The present study was undertaken to elucidate time-dependent serial transcript patterns in the HeLa cervical carcinoma cell line, following treatment with Zeocin. The HeLa cell proliferation rate was found to gradually decrease following Zeocin exposure, in a time-and dose-dependent manner. RNA transcript level measurements, for time-dependent serial gene expression profiling, were determined at 0, 6, 12, 18 and 24 hr using a 0.5 k apoptosis functional microarray chip. Further statistical analysis, using a significance test at a 95% confidence level, for transcripts with a greater than 2-fold change on the array chips, identified 49 up-regulated and 57 down-regulated genes. Our gene expression profile data indicate that Zeocin treatment induces an initial release of cytochrome c, the down-regulation of Bcl-X (L), ENDOG, DAXX and MDM2, and the up-regulation of CASP and BID. This suggests that a p53-independent mitochondrial caspase cascade pathway is primarily involved in Zeocin-induced apoptosis. Such caspasedependent cytotoxic activity also implies that this cell death pathway occurs via the caspase 8 and BID genes. However, disruption of either FAS or TNFR1 signaling did not interfere with the Zeocin induced apoptotic response in our experimental system. We hypothesize that Zeocin could be active against cervical cancer cell resistance to conventional chemotherapy and postulate that Zeocin is a novel candidate for the development of new chemotherapeutic treatments of gynecological cancers.
authors.affiliation: National Genome Research Institute, NIH, Seoul, Korea.
authors.forename: Jooyeon
authors.initials: J
authors.lastname: Hwang
authors.forename: Young-Youl
authors.initials: YY
authors.lastname: Kim
authors.forename: Sungjin
authors.initials: S
authors.lastname: Huh
authors.forename: Junghee
authors.initials: J
authors.lastname: Shim
authors.forename: Chan
authors.initials: C
authors.lastname: Park
authors.forename: Kuchan
authors.initials: K
authors.lastname: Kimm
authors.forename: Dong Kug
authors.initials: DK
authors.lastname: Choi
authors.forename: Tae-Kyu
authors.initials: TK
authors.lastname: Park
authors.forename: Soonhag
authors.initials: S
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D001761:Bleomycin / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors; D051020:bcl-X Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C088424:Cux1 protein, rat; D003598:Cytoskeletal Proteins; C106985:DAXX protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014157:Transcription Factors; D051020:bcl-X Protein; D001761:Bleomycin; C105427:Zeocin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020169:Caspases