Diverse effects of methylseleninic acid on the transcriptional program of human prostate cancer cells
Diverse effects of methylseleninic acid on the transcriptional program of human prostate cancer cells
复制标题
DOI：
10.1091/mbc.e03-07-0501
复制
发表时间：
2004-02-01
影响因子：
3.3
通讯作者：
Brooks, JD
中科院分区：
文献类型：
--
作者：
Zhao, HJ;Whitfield, ML;Brooks, JD
甲基硒酸（MSA）已被证明具有有效的抗癌活性，是研究硒体外抗癌作用的优秀化合物。为了深入了解 MSA 对前列腺癌的影响，我们表征了 LNCaP 的整体转录反应。通过使用高密度 cDNA 微阵列，将雄激素敏感的人前列腺癌细胞系转化为 MSA。我们鉴定了 951 个基因，其表达在 48 小时内响应 3-30 muM MSA，表现出惊人的剂量和时间依赖性变化。许多细胞周期调节基因的转录水平会因 MSA 的反应而发生变化，表明 MSA 会抑制增殖。与这些基因表达变化一致，通过羧基荧光素琥珀酰亚胺酯染色监测的细胞增殖在MSA处理后减少，并且通过流式细胞术检测到G0/G1期细胞的积累。令人惊讶的是，MSA 还调节许多雄激素调节基因的表达，在 mRNA 和蛋白质水平抑制雄激素受体 (AR) 表达，并降低分泌到培养基中的前列腺特异性抗原的水平。低浓度的 MSA 还诱导 2 相解毒酶转录水平显着增加，并诱导 NADPH 脱氢酶、醌 1 酶活性（总体 2 相酶活性的替代标记）。我们的结果表明，MSA 可能通过抑制细胞增殖、调节 AR 和 AR 调节基因的表达以及诱导致癌物防御来预防前列腺癌。
Methylseleninic acid (MSA) has been shown to have potent anticancer activity and is an excellent compound for studying the anticancer effects of selenium in vitro. To gain insights into the effects of MSA in prostate cancer, we characterized the global transcriptional response of LNCaP. an androgen-sensitive human prostate cancer cell line, to MSA by using high-density cDNA microarrays. We identified 951 genes whose expression shows striking dose- and time-dependent changes in response to 3-30 muM MSA over the time course of 48 h. Transcript levels of many cell cycle-regulated genes change in response to MSA, suggesting that MSA inhibits proliferation. Consistent with these gene expression changes, cell proliferation, monitored by carboxyfluoroscein succinimidyl ester staining, was decreased after MSA treatment, and an accumulation of cells at G0/G1 phase was detected by flow cytometry. Surprisingly, MSA also modulated expression of many androgen-regulated genes, suppressed androgen receptor (AR) expression at both mRNA and protein level, and decreased levels of prostate specific antigen secreted into the medium. Low concentrations of MSA also induced significant increases in transcript levels of phase 2 detoxification enzymes and induced NADPH dehydrogenase, quinone 1 enzymatic activity, a surrogate marker of global phase 2 enzyme activity. Our results suggest that MSA may protect against prostate cancer by inhibiting cell proliferation, by modulating the expression of AR and AR-regulated genes and by inducing carcinogen defenses.