Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line
- Department of Pharmacology and Toxicology, University of Oulu, FI-90014 Oulu (Finland)
- Department of Clinical Chemistry, University of Oulu, FI-90014 Oulu (Finland)
- Department of Pharmacology and Toxicology, University of Kuopio, FI-70211 Kuopio (Finland)
- Department of Obstetrics and Gynecology, University of Oulu, FI-90014 Oulu (Finland)
- Department of Pharmacology and Toxicology, University of Oulu, FI-90014 Oulu (Finland) and Department of Pharmacology and Toxicology, University of Kuopio, FI-70211 Kuopio (Finland)
p14{sup ARF} tumor suppressor protein regulates p53 by interfering with mdm2-p53 interaction. p14{sup ARF} is activated in response to oncogenic stimuli but little is known of the responses of endogenous p14{sup 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{sup 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{sup 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{sup ARF} can respond to DNA damage without oncogene activation in cell lines without functional p53.
- OSTI ID:
- 20850430
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 216; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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