2006 Fiscal Year Final Research Report Summary
Role of activin in cell proliferation, differentiation, and carcinogenesis in the prostate and kidney
| Project/Area Number |
17591665
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KIHARA Kazunori Tokyo Medical and Dental University, Graduate School, Professor, 大学院医歯学総合研究科, 教授 (40161541)
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| Project Period (FY) |
2005 – 2006
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| Keywords | activin / differentiation / prostate cancer / prostate specific antigen / renal cancer |
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| Research Abstract |
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
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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
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Research Products
(8 results)
