p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3.
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.
Wong
Ronald Pak Cheung
RP
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.
Tsang
Wing Pui
WP
Chau
Pui Yee
PY
Co
Ngai Na
NN
Tsang
Tsun Yee
TY
Kwok
Tim Tak
TT
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*
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D053148:Caspase 3; D008727:Methotrexate