Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line

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• 作者：Liisa Vaskivuo ; Jaana Rysä ; Johanna Koivuperä ; Pä ; ivi Myllynen ; Tommi Vaskivuo ; Katerina Chvalova ; Raisa Serpi ; Eeva-Riitta Savolainen ; Ulla Puistola and Kirsi Vä ; hä ; kangas
• 关键词：p14^ARF ; p53 ; Cisplatin ; Docetaxel ; Azidothymidine
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2006
• 期刊代码：58_0041008x
• 类别：pha
• 出版时间：1 October 2006
• 卷：216
• 期：1
• 页码：89-97
• 文件大小：460 K

摘要

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.