Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells.
Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells.
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DOI：
10.1186/1755-8794-2-55
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发表时间：
2009-08-20
影响因子：
2.7
通讯作者：
Peehl DM
中科院分区：
文献类型：
--
作者：
Zhao H;Flamand V;Peehl DM
单胺氧化酶A （MAO-A）是一种线粒体酶，可降解包括神经递质在内的单胺，在正常人前列腺上皮基底细胞和低分化（Gleason分级4和5）侵袭性前列腺癌（PCa）中高度表达。clogyline是一种MAO-A抑制剂，可诱导正常前列腺细胞分泌分化。我们检测了clyline对高级别PCa （E-CA）上皮细胞转录程序的影响。我们使用高密度寡核苷酸芯片系统地评估了clogyline在E-CA细胞中诱导的基因表达变化。通过微阵列显著性分析鉴定处理细胞和对照细胞中差异表达的基因。通过实时定量聚合酶链反应验证感兴趣基因的表达。通过微阵列显著性分析（SAM）， 156个基因的表达在6 ~ 96小时的时间内被clorgyline显著增加。该列表包含了从文献中编译的12个致癌途径特征中的7个被抑制的基因。此外，clyyline下调≥2倍的基因与β -catenin、ERBB2等关键癌基因上调的基因显著富集，表明clyyline具有抑癌作用。clyline的另一个显著作用是诱导雄激素受体（AR）和经典AR靶基因，如前列腺特异性抗原，以及其他分泌性上皮细胞特异性基因，提示clyline促进癌细胞分化。此外，clogyline下调了Polycomb Group （PcG）复合物的关键成分EZH2，该复合物抑制分化相关基因的表达。事实上，clorgyline上调了PcG抑制信号中预测PCa结果的许多基因，这表明clorgyline的促进分化作用可能是通过其下调EZH2介导的。我们的研究结果表明，已经用于治疗抑郁症的MAO-A抑制剂可能通过抑制致癌途径活性和促进分化而具有潜在的应用前景。
Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA). We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction. The expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2. Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
多种致癌途径特征显示人类前列腺肿瘤中的坐标表达模式。
影响因子：
3.7
作者：
Creighton, Chad J.
通讯作者：
Creighton, Chad J.
影响因子：
14.9
作者：
Li TH;Zhao H;Peng Y;Beliakoff J;Brooks JD;Sun Z
通讯作者：
Sun Z
影响因子：
4.4
作者：
Li CF;MacDonald JR;Wei RY;Ray J;Lau K;Kandel C;Koffman R;Bell S;Scherer SW;Alman BA
通讯作者：
Alman BA
影响因子：
6
作者：
Liu, AY;True, LD
通讯作者：
True, LD