Activins are multifunctional growth and differentiation factors, and stimulate follicle-stimulating hormone (FSH)- 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, 5 ^. -dihydrotestosterone (DHT) with or without their antagonists (follistatin, or nonsteroidal antiandrogen bicalutamide). Activin 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.