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

激活素是一种多功能生长和分化因子，通过垂体促性腺激素刺激卵泡刺激素(FSH)-β基因表达和FSH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着重要作用，是前列腺癌的重要肿瘤标志物。因此，PSA的调控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生成的直接影响，LNCaP细胞具有激活素受体和雄激素受体的功能，以及PSA。LNCaP细胞用激活素A、5α-二氢睾酮（DHT）联合或不联合其拮抗剂（卵泡抑素或非甾体抗雄激素比卡鲁胺）处理。激活素A对LNCaP细胞的抑制作用呈剂量依赖性，而DHT对LNCaP细胞的抑制作用呈双相增加。与激活素A和DHT对细胞生长的作用相反，激活素A和DHT均上调LNCaP细胞的PSA基因表达，增加PSA分泌。激活素A和二氢睾酮增加PSA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生成无影响。激活素A对LNCaP细胞的作用被卵泡素抑制而非比卡鲁胺抑制，DHT的作用被比卡鲁胺抑制而非卵泡素抑制。激活素A通过不依赖雄激素受体的途径上调PSA的产生。激活素/卵泡抑素系统可能是前列腺组织中PSA基因转录和分泌的生理调节剂，激活素可能与雄激素协同在体内上调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，并且在激活素处理一周后，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了细胞的不可逆分化。此外，激活素对LNCaP细胞的生长有轻微的抑制作用。此外，在另一项实验中，我们发现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il - 8 mRNA表达及蛋白分泌，从而抑制体内肿瘤生长，低剂量口服DEX可达到体内浓度。少

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