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Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin
Author(s) -
Yonesaka Kimio,
Tamura Kenji,
Kurata Takayasu,
Satoh Taroh,
Ikeda Masato,
Fukuoka Masahiro,
Nakagawa Kazuhiko
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21350
Subject(s) - survivin , small interfering rna , cancer research , apoptosis , biology , cell culture , cell growth , inhibitor of apoptosis , cancer cell , microbiology and biotechnology , chemistry , cancer , transfection , programmed cell death , biochemistry , genetics
Survivin is a member of the inhibitor of apoptosis protein (IAP) family that is specifically overexpressed in cancer tissues. p53 is one of the tumor suppressor genes; its induction in response to DNA damage causes apoptosis and correlates with drug sensitivity. To investigate the possible regulation of survivin by p53, we examined the level of survivin expression in lung cancer cell lines in response to adriamycin. Levels of survivin mRNA and protein in cell lines with wild‐type p53 decreased dramatically after p53 induction, but no such reduction of survivin was observed in cell lines with mutated or null p53. Inhibition of wild‐type p53 in A549 cells by small interfering (si) RNA significantly upregulated the expression of survivin. Survivin inhibition by siRNA in PC9 cells with mutated p53 significantly depressed cell proliferation. To investigate the sensitivity of cancer cells to adriamycin after inhibition of survivin, we depressed survivin expression using siRNA, and then added adriamycin at an IC 50 dose. After a further 48 hr incubation with adriamycin, proliferation was significantly depressed in the cells treated with siRNA targeting survivin, in comparison with siRNA targeting scramble. Furthermore, both TUNEL and pro‐caspase3 expression assay showed a significant increase in apoptosis after combined treatment with adriamycin and siRNA targeting survivin. Our results demonstrate that survivin is downregulated by p53, and that siRNA targeting of survivin increases cell sensitivity to adriamycin and promotes apoptosis. siRNA targeting of survivin could be potentially useful for increasing sensitivity to anticancer drugs, especially in drug‐resistant cells with mutated p53. © 2005 Wiley‐Liss, Inc.