Suppression of cell proliferation and regulation of estrogen receptor α signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells
Suppression of cell proliferation and regulation of estrogen receptor α signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells
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DOI：
10.1677/joe.0.1820325
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发表时间：
2004-08-01
影响因子：
4
通讯作者：
Fung, KP
中科院分区：
文献类型：
--
作者：
Chow, SKY;Chan, JYW;Fung, KP
近年来，乳腺癌引起了人们的广泛关注。随着世界各地发病率的不断上升，对乳腺癌患者最常用的化疗药物他莫昔芬的耐药性的发展突出了开发新的化疗药物对抗乳腺癌的重要性。以治疗乳腺癌为目的，研究了三氧化二砷对MCF-7细胞的抗肿瘤作用。采用MTT法和直接细胞计数法检测细胞增殖情况。通过测定雌激素受体（ER）结合率、ER α mRNA和蛋白水平及其活性，阐明了三氧化二砷的作用机制，并证实了三氧化二砷通过抑制雌激素诱导的MCF-7细胞生长刺激效应，降低MCF-7细胞的存活率。三氧化二砷通过调节ER α信号通路抑制雌激素的作用。三氧化二砷可下调ER α、mRNA和蛋白水平，而不与雌激素竞争ER α结合。三氧化二砷还可抑制ER α信号通路介导的转录活性，最终下调c-myc蛋白的表达，抑制雌激素刺激下的细胞进入S期，从而抑制MCF-7细胞的生长。雌激素是促进乳腺癌细胞生长的主要危险因素，三氧化二砷的抗雌激素活性为乳腺癌的治疗提供了新的思路。
In recent years, breast cancers have aroused much concern. Together with a growing incidence all over the world, the development of drug resistance to tamoxifen, the most commonly prescribed chemotherapeutic drug for breast cancer patients, has highlighted the importance of developing a new chemotherapeutic drug in combating breast cancer. With the aim of treating breast cancers, the anti-tumor effects of arsenic trioxide in MCF-7 cells have been studied.MCF-7 cells are estrogen responsive cells which mimic breast cancers at the early stage. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and direct cell counting were used to measure cell proliferation. The mechanisms of action were elucidated through the measurement of estrogen receptor (ER) binding, mRNA and protein levels of ERalpha and its activity.We have demonstrated that arsenic trioxide was capable of reducing cell survival in MCF-7 cells via the suppression of the estrogen-induced growth stimulatory effects in MCF-7 cells. Arsenic trioxide was shown to suppress the action of estrogen through the regulation of the ERalpha signaling pathway. Arsenic trioxide could downregulate ERalpha, mRNA and protein levels without competing with estrogen for ERalpha, binding. Arsenic trioxide also inhibited the transcription activity mediated by the ERalpha, signaling pathway and ultimately it down-regulated c-myc protein expression and inhibited cell entry to S phase under estrogen's stimulation.In conclusion, arsenic trioxide could inhibit the growth of MCF-7 cells by reducing the growth stimulatory effect of estrogen. As estrogen is a primary risk factor in promoting the growth of breast tumor cells, the antiestrogenicity exhibited by arsenic trioxide sheds light on the therapy of breast cancer.