p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3
| Autor: | Ronald Pak Cheung Wong, Ngai Na Co, Wing Pui Tsang, Tsun Yee Tsang, Pui Yee Chau, Tim Tak Kwok |
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| Rok vydání: | 2007 |
| Předmět: |
Antimetabolites
Antineoplastic Cancer Research Small interfering RNA Down-Regulation Apoptosis Bone Neoplasms Drug resistance Pharmacology Biology Transfection Gene Expression Regulation Enzymologic Downregulation and upregulation Tumor Cells Cultured medicine Humans RNA Small Interfering Osteosarcoma Gene knockdown Antibiotics Antineoplastic Caspase 3 Cancer medicine.disease Gene Expression Regulation Neoplastic Methotrexate Oncology Doxorubicin Drug Resistance Neoplasm Mutation Carcinoma Squamous Cell Cancer research Tumor Suppressor Protein p53 A431 cells |
| Zdroj: | Molecular Cancer Therapeutics. 6:1054-1061 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-06-0336 |
| Popis: | Development of drug resistance is one of the major obstacles in cancer chemotherapy. The molecular mechanism leading to drug resistance is still not fully understood. A10A cells, a doxorubicin-resistant subline of human squamous cell carcinoma A431 cells, showed cross-resistance to methotrexate and also resistance to the drug-induced apoptosis. The cells also showed overexpression of a mutated form of p53, p53-R273H (Arg to His at codon 273), and down-regulation of procaspase-3. Knockdown of p53-R273H by p53 small interfering RNA in A431 cells increased procaspase-3 level and sensitized the cells to drug-induced apoptosis. On the other hand, transfection of p53-R273H into p53 null human osteosarcoma Saos-2 cells down-regulated procaspase-3 level and induced resistance to the drug toxicity and drug-induced apoptosis. The results support the idea that p53-R273H may gain new functions in induction of drug resistance and impairment in drug-induced apoptosis through down-regulation of procaspase-3 level. The study sheds new light on the understanding of the gain of function and drug resistance mechanisms associated with mutant p53. [Mol Cancer Ther 2007;6(3):1054–8] |
| Databáze: | OpenAIRE |
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