CONTROL OF LNCAP PROLIFERATION AND DIFFERENTIATION - ACTIONS AND INTERACTIONS OF ANDROGENS, 1-ALPHA,25-DIHYDROXYCHOLECALCIFEROL, ALL-TRANS-RETINOIC ACID, 9-CIS RETINOIC ACID, AND PHENYLACETATE

There is increasing evidence that growth and differentiation of prosta tic carcinoma cells may be modulated not only by androgens and growth factors but also by vitamin D, retinoids, and phenylacetate (PA). The latter agonists may have a role in the prevention and therapy of prost ate cancer but their exact therapeutic potential remains unclear. Sinc e both retinoids and vitamin D act via nuclear receptors, the same way androgens do, we studied the interactions of these compounds with and rogen-induced proliferation and differentiation using LNCaP cells as a model. of androgen-responsive tumor cells. PA was included because of its suspected different mode of action. [H-3]-thymidine incorporation was used as a measure of proliferative activity, secretion of prostat e-specific antigen (PSA) as a measure of differentiated function. The present data show that 1 alpha,25-dihydroxycholecalciferol (VD3), all- trans retinoic acid (atRA), 9-cis retinoic acid (9cRA), and PA stimula ted LNCaP cell-differentiated function in the presence or absence of a ndrogens. The effects on cell growth were more complicated. In the abs ence of androgens growth stimulatory effects were observed for the ret inoids and under some conditions for VD3. These effects were limited, however, and tended to be more pronounced at low cell densities. In th e presence of androgens nearly exclusively growth inhibitory effects w ere observed. On a molar basis VD3 was the most effective antiprolifer ative agonist (ED(50) = 10(-9) M). It completely neutralized the stimu latory effects of androgens. Growth inhibition was not due to a decrea se in the concentration of androgen receptor: whereas atRA, 9cRA, and PA did not alter androgen receptor levels, VD3 provoked a twofold incr ease. Neither in the presence nor in the absence of androgens did we o bserve any cooperativity in the growth stimulatory or inhibitory effec ts of VD3, atRA, or 9cRA. To test whether treatment with any of the st udied agonists resulted in a phenotypic reversion and sustained growth arrest, LNCaP cells were pretreated with VD3, atRA, 9cRA, or PA for 6 -12 days and reseeded at equal densities as untreated cells. In all ca ses tested [H-3]-thymidine incorporation was restored within 6 days su ggesting that none of these compounds caused irreversible growth inhib ition. (C) 1996 Wiley-Liss, Inc.