Targeting monoamine oxidase A in advanced prostate cancer.
Targeting monoamine oxidase A in advanced prostate cancer.
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DOI：
10.1007/s00432-010-0835-6
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发表时间：
2010-11
影响因子：
3.6
通讯作者：
Peehl, Donna M.
中科院分区：
文献类型：
--
作者：
Flamand, Vincent;Zhao, Hongjuan;Peehl, Donna M.
单胺氧化酶 A (MAOA) 抑制剂是一种线粒体酶，可降解包括血清素和去甲肾上腺素在内的神经递质，通常用于治疗包括抑郁症在内的神经系统疾病。最近，我们和其他人发现 MAOA 在正常基底前列腺上皮和高级别原发性前列腺癌 (PCa) 中高表达。相反，MAOA 在正常分泌性前列腺上皮和低级别 PCa 中含量较低。 MAOA 的不可逆抑制剂氯吉林可诱导正常基底上皮细胞和高级 PCa 的原代培养物的分泌分化。此外，氯吉兰抑制 PCa 细胞中的多种致癌途径，表明 MAOA 抑制剂作为高危 PCa 的促分化和抗癌治疗的临床价值。在这里，我们将研究扩展到晚期前列腺癌 VCaP 细胞模型，这些细胞源自去势抵抗性转移性前列腺癌，表达高水平的 MAOA。在体外和体内评估了存在或不存在氯吉林时 VCaP 细胞的生长。通过微阵列测定响应氯吉林的基因表达变化，并通过定量实时聚合酶链反应进行验证。体外用氯吉林处理可抑制 VCaP 细胞的生长并改变其转录模式，其方式与处理的原代 PCa 细胞中观察到的促分化和抗癌作用一致。与雄激素非依赖性生长和转移有关的 Src、β-连环蛋白和 MAPK 致癌途径显着下调。对携带 VCaP 异种移植物的小鼠进行氯吉兰治疗可减缓肿瘤生长并诱导转录组变化，与体外观察到的情况类似。我们的结果支持了这样一种可能性：针对 MAOA 的抗抑郁药物可能在治疗 PCa 方面找到新的应用。
Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA. Growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time polymerase chain reaction. Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen-independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro. Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa.
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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：
3.4
作者：
Pietrangeli, P;Mondovì, B
通讯作者：
Mondovì, B
DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
影响因子：
6
作者：
Liu, AY;True, LD
通讯作者：
True, LD
影响因子：
7.3
作者：
Chiou, Shih-Hwa;Ku, Hung-Hai;Chang, Yuh-Lih
通讯作者：
Chang, Yuh-Lih