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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

激活素是一种多功能的生长分化因子，能刺激促性腺激素促性腺激素β基因表达和促性腺激素分泌。卵泡抑素与激活素结合，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着重要作用，也是前列腺癌的重要肿瘤标志物。因此，对PSA的调控具有重要的临床意义。前人研究表明，PSA主要受雄激素的调节。在先前的研究中，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，激活素受体和雄激素受体发挥作用，以及PSA。用激活素A，5-二氢睾酮(α-dihytesterone，DHT)加或不加其拮抗剂(卵泡抑素或非甾体抗雄激素比卡鲁胺)处理LNCaP细胞。激活素A de…LNCaP细胞生长呈剂量依赖关系，DHT呈双时相增加。激活素A和DHT均上调LNCaP细胞PSA基因的表达，增加PSA的分泌，而对细胞生长的作用相反。激活素A和DHT对PSA产量的促进作用是协同或相加的。卵泡抑素和比卡鲁胺对细胞生长和PSA产生均无影响。激活素A对LNCaP细胞的作用可被卵泡抑素阻断，而比卡鲁胺不能阻断激活素对LNCaP细胞的作用；激活素A上调PSA的产生，其作用是通过雄激素受体非依赖性途径实现的。激活素/卵泡抑素系统是前列腺组织中PSA基因转录和分泌的生理调节因子，激活素可能与雄激素在体内协同上调PSA。本研究表明，在无雄激素的情况下，激活素完全抑制LNCaP细胞的增殖，经激活素处理一周后，雄激素再也无法恢复细胞的增殖。包括PSA在内的分化标志物提示激活素诱导了细胞的不可逆分化。此外，在另一项实验中，我们还发现，在口服低剂量地塞米松的体内浓度下，糖皮质激素可能通过糖皮质激素受体途径抑制前列腺细胞血管内皮生长因子(VEGF)和IL8mRNA的表达和蛋白质分泌，从而抑制体内肿瘤的生长。较少