Resveratrol protects leukemic cells against cytotoxicity induced by proteasome inhibitors via induction of FOXO1 and p27Kip1.
Resveratrol protects leukemic cells against cytotoxicity induced by proteasome inhibitors via induction of FOXO1 and p27Kip1.
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DOI：
10.1186/1471-2407-11-99
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发表时间：
2011-03-19
期刊：
影响因子：
3.8
通讯作者：
Wang HQ
中科院分区：
文献类型：
--
作者：
Niu XF;Liu BQ;Du ZX;Gao YY;Li C;Li N;Guan Y;Wang HQ
近年来研究发现，白藜芦醇可使多种肿瘤细胞对某些常规化疗药物产生敏感性。本研究旨在探讨白藜芦醇是否能使白血病细胞对蛋白酶体抑制剂敏感。白血病细胞用MG 132单独或与白藜芦醇组合处理。MTT法检测细胞活力，流式细胞仪检测细胞凋亡和细胞周期分布。Western blot和real-time RT-PCR检测FOXO 1和p27 Kip 1的表达。用CHIP法研究FOXO 1与p27 Kip 1启动子的结合。白藜芦醇强烈降低蛋白酶体抑制剂对白血病细胞的细胞毒活性。MG 132与白藜芦醇联合使用通过p27 Kip 1积累在G1/S转换处引起细胞周期阻滞。使用siRNA敲低p27 Kip 1显著减弱白藜芦醇对蛋白酶体抑制剂对白血病细胞的细胞毒性作用的保护作用。白藜芦醇在转录水平诱导FOXO 1的表达，而MG 132增加FOXO 1的核分布。MG 132与白藜芦醇组合通过增加p27 Kip 1启动子上FOXO 1的募集而引起p27 Kip 1的协同诱导。白藜芦醇可能通过调节FOXO 1转录活性和p27 Kip 1积累来抵消蛋白酶体抑制剂的细胞毒性作用。
It was reported recently that resveratrol could sensitize a number of cancer cells to the antitumoral effects of some conventional chemotherapy drugs. The current study was designed to investigate whether resveratrol could sensitize leukemic cells to proteasome inhibitors. Leukemic cells were treated with MG132 alone or in combination with resveratrol. Cell viability was investigated using MTT assay, and induction of apoptosis and cell cycle distribution was measured using flow cytometry. Western blot and real-time RT-PCR were used to investigate the expression of FOXO1 and p27Kip1. CHIP was performed to investigate the binding of FOXO1 to the p27 Kip1 promoter. Resveratrol strongly reduced cytotoxic activities of proteasome inhibitors against leukemic cells. MG132 in combination with resveratrol caused cell cycle blockade at G1/S transition via p27Kip1 accumulation. Knockdown of p27Kip1 using siRNA dramatically attenuated the protective effects of resveratrol on cytotoxic actions of proteasome inhibitors against leukemic cells. Resveratrol induced FOXO1 expression at the transcriptional level, while MG132 increased nuclear distribution of FOXO1. MG132 in combination with resveratrol caused synergistic induction of p27Kip1 through increased recruitment of FOXO1 on the p27Kip1 promoter. Resveratrol may have the potential to negate the cytotoxic effects of proteasome inhibitors via regulation of FOXO1 transcriptional activity and accumulation of p27Kip1.
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