EXPRESSION OF NOVEL GENES LINKED TO THE ANDROGEN-INDUCED, PROLIFERATIVE SHUTOFF IN PROSTATE-CANCER CELLS

Androgens control cell numbers in the prostate through three separate pathways: (a) inhibition of cell death, (b) induction of cell prolifer ation (Step-1) and (c) inhibition of cell proliferation (Step-2, proli ferative shutoff). The mechanisms underlying these phenomena are incom pletely understood. The human prostate carcinoma LNCaP variants expres s these pathways as follows: LNCaP-FGC express both steps, LNCaP-LNO e xpresses Step-2, LNCaP-TAC expresses Step-1, and LNCaP-TJA cells expre ss neither step. These cells facilitated the search for mediators of t he androgen-induced proliferative shutoff pathway. Androgen exposure f or 24 h or longer induced an irreversible proliferative shutoff in LNC aP-FGC cells. The Wang and Brown approach for identifying differential ly expressed mRNAs was used to search for mediators of Step-2. Ten uni que inserts were identified and from those ten, three genes were furth er studied. The basal expression of these genes in shutoff-negative va riants was not affected by androgen exposure. They were induced by and rogens in shutoff-positive LNCaP variants and the androgen receptor-tr ansfected, shutoff-positive, MCF7-AR1 cells. These genes were induced only in the range of androgen concentrations that elicited the shutoff response. Time course analysis showed that their induction precedes t he commitment point by 12-18 h. In addition, they were expressed in th e normal prostate during proliferative shutoff. These features suggest that the candidate genes have a role in the regulation cascade for pr oliferative shutoff. (C) 1997 Published by Elsevier Science Ltd. All r ights reserved.