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

激活素在前列腺和肾脏细胞增殖、分化和癌变中的作用

基本信息

批准号：
17591665
负责人：
KIHARA Kazunori
金额：
$ 1.66万
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：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

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. Previsous studies showed that PSA is primarily regulated by andorogens. In the previous study, we evaluated the direct effects of activin A on the proliferation and PSA production of prostate cancer LNCaP cells, which 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 A de … More creased 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.In the present study, we have shown that activin completely inhibited the proliferation of LNCaP cells in the absence of androgens, and after one week treatment of activin, androgen never recovered the proliferation of the cells. Differentiation markers including PSA suggested that activin induced the non-reversible differentiation of the cells. Further, activin slightly inhibited the growth of LNCaP cells in vivo models.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 endothelial growth factor (VEGF) and IL8 mRNA expression and protein secretion of prostate cells possibly through the glucocorticoid receptor pathway, and suppress in vivo tumor growth. Less

激活素是多功能生长和分化因子，可刺激促卵泡激素 (FSH)-β 基因表达和垂体促性腺激素分泌 FSH。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）在男性生殖生理学中发挥着重要作用，并且作为前列腺癌的肿瘤标志物非常重要。因此，PSA的调节具有重要的临床意义。先前的研究表明，PSA 主要受雄激素的调节。在之前的研究中，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，该细胞具有激活素受体和雄激素受体以及 PSA 的功能。 LNCaP 细胞用激活素 A、5α-二氢睾酮 (DHT) 联合或不联合其拮抗剂（卵泡抑素或非类固醇抗雄激素比卡鲁胺）进行处理。 Activin A de … 更多以剂量依赖性方式增加 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（而非比卡鲁胺）阻断，而 DHT 的作用被比卡鲁胺（而非卵泡抑素）阻止。激活素 A 上调 PSA 的产生，其作用是通过雄激素受体独立途径实现的。激活素/卵泡抑素系统可以作为前列腺组织中PSA基因转录和分泌的生理调节剂，并且激活素可能与雄激素协同上调体内PSA。在本研究中，我们发现在没有雄激素的情况下，激活素完全抑制LNCaP细胞的增殖，并且在激活素治疗1周后，雄激素再也没有恢复细胞的增殖。包括 PSA 在内的分化标记表明激活素诱导细胞的不可逆分化。此外，激活素在体内模型中轻微抑制LNCaP细胞的生长。此外，在另一项实验中，我们已经表明，糖皮质激素在体内口服低剂量DEX可达到的浓度下，可能通过糖皮质激素受体途径对血管内皮生长因子（VEGF）和IL8 mRNA表达以及前列腺细胞的蛋白质分泌具有抑制作用，并抑制体内肿瘤生长。较少的