title: Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line.
abstract: p14(ARF) tumor suppressor protein regulates p53 by interfering with mdm2-p53 interaction. p14(ARF) is activated in response to oncogenic stimuli but little is known of the responses of endogenous p14(ARF) to different types of cellular stress or DNA damage. Azidothymidine (AZT) is being tested in several clinical trials as an enhancer of anticancer chemotherapy. However, the knowledge of the relationship between AZT and cellular pathways, e.g. p53 pathway, is very limited. In this study, we show that AZT, cisplatin (CDDP) and docetaxel (DTX) all induce unique molecular responses in OVCAR-3 ovarian carcinoma cells carrying a mutated p53, while in A2780, ovarian carcinoma and MCF-7 breast carcinoma cells with wild type p53, all of these drugs cause similar p53 responses. We found that endogenous p14(ARF) protein in OVCAR-3 cells is down-regulated by DTX but induced by AZT and a short CDDP pulse treatment. In HT-29 colon carcinoma cells with a mutated p53, all treatments down-regulated p14(ARF) protein. Both CDDP and AZT increased the expression of p14ARF mRNA in OVCAR-3 cells. Differences in cell death induced by these drugs did not explain the differences in protein and mRNA expressions. No increase in the level of either c-Myc or H-ras oncoproteins was seen in OVCAR-3 cells after AZT or CDDP-treatment. These results suggest that p14(ARF) can respond to DNA damage without oncogene activation in cell lines without functional p53.
authors.affiliation: Department of Pharmacology and Toxicology, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Vaskivuo
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
authors.forename: Johanna
authors.initials: J
authors.lastname: Koivuperä
authors.forename: Päivi
authors.initials: P
authors.lastname: Myllynen
authors.forename: Tommi
authors.initials: T
authors.lastname: Vaskivuo
authors.forename: Katerina
authors.initials: K
authors.lastname: Chvalova
authors.forename: Raisa
authors.initials: R
authors.lastname: Serpi
authors.forename: Eeva-Riitta
authors.initials: ER
authors.lastname: Savolainen
authors.forename: Ulla
authors.initials: U
authors.lastname: Puistola
authors.forename: Kirsi
authors.initials: K
authors.lastname: Vähäkangas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D055291:Salivary alpha-Amylases; D043823:Taxoids / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D004268:DNA-Binding Proteins; D000077143:Docetaxel; D047908:Intracellular Signaling Peptides and Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors; D055291:Salivary alpha-Amylases; D043823:Taxoids; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D015215:Zidovudine; D018631:ras Proteins; D000097642:GADD45 Proteins; C524799:Amy1 protein, mouse