Enhancement of androgen-dependent transcription and cell proliferation by tributyltin and triphenyltin in human prostate cancer cells

Tributyltin (TBT) and triphenyltin (TPT) are known to cause imposer, the su perimposing of male genitals on female ones, in some species of gastropods. However, the molecular mechanism of the trialkyltin-induced endocrine dysf unction remains to be elucidated. To clarify the effects of organotin compo unds on the activation of androgen receptor (AR)-mediated responses in mamm als, a LA16 clone that stably expresses androgen-responsive luciferase repo rter gene and proliferates in response to androgen was established from hum an prostate cancer cell line LNCaP. Stimulation of LA16 cells with 100 nM T BT or 1 nM TPT enhanced both AR-dependent transcription of luciferase gene and cell growth to the same extent as those by 1 nM dihydrotestosterone (DH T). TBT or TPT also enhanced the DNA synthesis and expression of endogenous AR target genes such as prostate specific antigen, but not the expression of AR itself. However, an androgen antagonist, flutamide, did not inhibit t he TBT- or TPT-induced AR activation. On the other hand, simultaneous treat ment of LA16 cells with DHT and TBT or TPT caused highly enhanced effects o n AR activation. These results indicate that trialkyltin compounds have an ability to activate AR-mediated transcription in mammalian cells and sugges t that a novel target site other than the ligand-binding site of AR is invo lved in this activation. (C) 2000 Academic Press.