Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models

Testosterone-repressed prostate message-2 (TRPM3) expression is highly up-r egulated in normal and malignant prostate cells after androgen withdrawal, Although recent studies have suggested a protective role of TRPM-2 expressi on against apoptosis in several experimental models, the functional role of TRPM-2 in chemotherapy-induced apoptosis remains undefined. Here, we demon strated that overexpression of TRPM-2 in human androgen-dependent LNCaP pro state cancer cells by stable transfection rendered them highly resistant to paclitaxel treatment than control LNCaP cells, with a 20-fold higher IC50 through the inhibition of apoptotic cell death. In mice bearing TRPM-2-over expressing LNCaP tumors, tumor volume and serum prostate-specific antigen i ncreased two to three times faster after castration and paclitaxel treatmen t compared with mice bearing control tumors, We then tested the efficacy of combined treatment with antisense TRPM3 oligodeoxynucleotide (ODN) and pac litaxel in the mouse androgen-dependent Shionogi tumor model, Antisense TRP M-2 ODN treatment significantly enhanced paclitaxel chemosensitivity of Shi onogi tumor cells in a dose-dependent manner, reducing the IC50 by 75%. Com bined treatment of Shionogi cells with 500 nM antisense TRPM-2 ODN and 10 n M paclitaxel-induced apoptosis, either agent alone did not. Adjuvant admini stration of antisense TRPM-2 ODN and polymeric micellar paclitaxel after ca stration resulted in reduced TRPM-2 levels in vivo and a significant delay of emergence of androgen-independent recurrent Shionogi tumors compared wit h administration of either agent alone. Furthermore, combined treatment of mice bearing androgen-independent recurrent Shionogi tumors with antisense TRPM-2 ODN and micellar paclitaxel inhibited tumor growth compared with tre atment with either agent alone. Collectively, these findings demonstrate th at TRPM-2 overexpression helps confer a chemoresistant phenotype through in hibition of apoptosis, and that antisense TRPM-2 ODN may be useful in enhan cing the effects of cytotoxic chemotherapy in hormone-refractory prostate c ancer.