title: p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3.
abstract: 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.
authors.affiliation: Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
authors.forename: Ronald Pak Cheung
authors.initials: RP
authors.lastname: Wong
authors.forename: Wing Pui
authors.initials: WP
authors.lastname: Tsang
authors.forename: Pui Yee
authors.initials: PY
authors.lastname: Chau
authors.forename: Ngai Na
authors.initials: NN
authors.lastname: Co
authors.forename: Tsun Yee
authors.initials: TY
authors.lastname: Tsang
authors.forename: Tim Tak
authors.initials: TT
authors.lastname: Kwok
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D053148:Caspase 3; D008727:Methotrexate