Molecular Mechanism of Cisplatin Resistance in Head and Neck Cancers
| Autor: | Kimitoshi Kohno, Hideaki Suzuki, Gunji Nagatani, Tetsuro Wakasugi, Hiroto Izumi, Jun-ichi Ohkubo |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Practica Oto-Rhino-Laryngologica. 104:161-170 |
| ISSN: | 1884-4545 0032-6313 |
| DOI: | 10.5631/jibirin.104.161 |
| Popis: | Cisplatin is a potent and pivotal anticancer drug in the treatment of various solid tumors including head and neck cancers. Since the beginning of its clinical use in the early 1980s, cisplatin has been one of the most prevailing and reliable anticancer drugs. Its major limitation, however, is the development of resistance during the courses of chemotherapy. The mode of action of cisplatin is mediated by the formation of DNA adducts, which activate several signal transduction pathways, eventually leading to cellular apoptosis. Cisplatin resistance depends on a number of factors that reduce drug uptake, promote cytoplasmic detoxification, and increase DNA repair activity. We herein review a novel mechanism of cisplatin resistance involving the transcriptional regulation of DNA repair genes by ZNF143. ZNF143 is overexpressed in cisplatin-resistant cells, and its knockdown increases sensitivity to cisplatin but not to oxaliplatin, etoposide, or vincristine. We show that ZNF143 is associated with p73, but not with p53. p73 enhances the action of ZNF143 by facilitating the binding of ZNF143 to ZNF143 binding sites and cisplatin-modified DNA. We further present direct evidence that DNA repair genes, Rad51 and FEN-1, are targeted by ZNF143 and overexpressed in cisplatin-resistant cells. These lines of evidence indicate that the interplay among ZNF143, p73, and ZNF143 target DNA repair genes is responsible for cisplatin resistance. Prediction of cisplatin sensitivity and molecular targeted therapy for ZNF143 remain to be conducted in future basic and clinical studies for managing cisplatin-resitant cancers. |
| Databáze: | OpenAIRE |
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