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Role of activin in cell proliferation, differentiation, and cardnogenesis in the prostate and kidney

激活素在前列腺和肾脏细胞增殖、分化和心脏发生中的作用

基本信息

批准号：
15591673
负责人：
FUJII Yasuhisa
金额：
$ 2.11万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591673/
关键词：
activin prostate specific antigen prostate cancer glucocorticoid renal cancer vascular endothelial growth factor prostate specific antigen prostate PSA LNCaP

项目摘要

Activins are multifunctional growth and differentiation factors, and stimulate follicle-stimulating hormone (FSH)-β gene expression and FSH secretion by the pituitary gonadotropes. Follistatins bind activin, resulting in the neutralization of activin bioactivity. Activin/follistatin system is present in the prostate tissue. Prostate specific antigen (PSA) plays an important role in male reproductive physiology as well as is very important as a tumor marker for prostate cancer. Thus, the regulation of PSA has important clinical implications. Previous studies showed that PSA is primarily regulated by androgens. In the present study, we evaluated the direct effects of activin A on the proliferation and PSA production of prostate cancer LNCaP cells, which express functional activin receptors and androgen receptor, and PSA. LNCaP cells were treated with activin A, 5α-dihydrotestosterone (DHT) with or without their antagonists (follistatin, or nonsteroidal antiandrogen bicalutamide). Activin … More A decreased cell growth of LNCaP cells in a dose-dependent manner while DHT increased in a biphasic manner. In contrast to their opposing actions on the cell growth, both activin A and DHT up-regulated PSA gene expression and increased PSA secretion by LNCaP cells. The effects of activin A and DHT to increase PSA production were synergistic or additive. Follistatin or bicalutamide was without effect on cell growth or PSA production. The effects of activin A on LNCaP cells were blocked by follistatin, not by bicalutamide, while those of DHT were prevented by bicalutamide, not by follistatin. Activin A up-regulates PSA production and the effect is through androgen receptor independent pathway. Activin/follistatin system can be a physiological modulator of PSA gene transcription and secretion in the prostate tissue, and activins may cooperate with androgen to up-regulate PSA in vivo.Further, in another experiment, we have shown that glucocorticoids, at concentrations achievable in vivo by oral administration of low doses of DEX, have an inhibitory effect on vascular endothelical growth factor (VEGF) mRNA expression and protein secretion of RCC cells possibly through the glucocorticoid receptor pathway. Less

激活素是一种多功能的生长和分化因子，可刺激促卵泡激素（FSH）-β基因表达和垂体促性腺激素分泌。卵泡抑素结合激活素，导致激活素生物活性的中和。激活素/卵泡抑素系统存在于前列腺组织中。前列腺特异性抗原（PSA）在男性生殖生理中起重要作用，同时也是前列腺癌的重要肿瘤标志物。因此，PSA的调节具有重要的临床意义。以往的研究表明，PSA主要受雄激素的调节。在本研究中，我们评估了激活素A对前列腺癌LNCaP细胞增殖和PSA产生的直接影响，LNCaP细胞表达功能性激活素受体和雄激素受体以及PSA。LNCaP细胞用激活素A、5α-二氢睾酮（DHT）和或不和其拮抗剂（卵泡抑素或非甾体抗雄激素比卡鲁胺）处理。激活素 ...更多信息 A以剂量依赖性方式降低LNCaP细胞的细胞生长，而DHT以双相方式增加。与它们对细胞生长的相反作用相反，激活素A和DHT均上调PSA基因表达并增加LNCaP细胞的PSA分泌。激活素A和DHT增加PSA产生的作用是协同的或相加的。卵泡抑素或比卡鲁胺对细胞生长或PSA产生没有影响。激活素A对LNCaP细胞的作用被卵泡抑素阻断，而不是被比卡鲁胺阻断，而DHT的作用被比卡鲁胺阻断，而不是被卵泡抑素阻断。激活素A通过雄激素受体非依赖性途径上调PSA的产生。激活素/卵泡抑素系统可以是前列腺组织中PSA基因转录和分泌的生理调节剂，并且激活素可以与雄激素合作在体内上调PSA。此外，在另一个实验中，我们已经表明，在通过口服低剂量DEX可达到的体内浓度下，抑制肾癌细胞血管内皮生长因子（VEGF）mRNA表达和蛋白分泌，可能通过糖皮质激素受体途径实现。少