In androgen-responsive LNCaP human prostatic cancer cells, human TR3 orphan receptor, a member of the steroid receptor superfamily, can be rapidly induced by androgen. In contrast, ablation of androgen by castration can induce the expression of the TR3 orphan receptor gene in rat ventral prostate that has undergone apoptosis. This phenomenon prompted us to further analyze the potential role of human TR3 orphan receptor in prostate cancer cells in which apoptosis had been induced. Northern blot analysis shows that human TR3 orphan receptor expression can be induced rapidly after treatment of LNCaP and PC-3 prostate cancer cells with calcium ionophore or etoposide. Our data further demonstrate that a much higher concentration of etoposide was needed to kill the same number of cells in LNCaP and PC-3 cells transfected stably with antisense TR3 orphan receptor compared with that in control vector transfectants. Together, our data suggest that the human TR3 orphan receptor may play an important role in modulating drug-induced prostate apoptosis.