Tyrosine kinase inhibitors reduce bcl-2 expression and induce apoptosis in androgen-dependent cells

The signal transduction pathway showing howandrogen withdrawal induces apoptosis in androgen-dependent cells hasnot been clearly understood. In these studies, we focusedon the behavior of tyrosine kinases in androgen-dependent cells andinvestigated its correlation with apoptosis and bcl-2 expression. Weused SC2G, an androgen-dependent mouse mammary carcinoma cell line,which had been cloned from Shionogi Carcinoma 115 (SC115). When SC2G cells were cultured with herbimycin A (HMA), a potent tyrosine kinaseinhibitor, the number of viable cells decreased significantly after 24 h. Terminal deoxyribonucleotidyltransferase-mediated dUTP-biotin nick end labeling and flow cytometric analysis of annexin Vstaining showed that HMA induced apoptosis of SC2G cells. The level ofbcl-2 mRNA in SC2G cells was suppressed by HMA in a dose-dependentmanner on RT-PCR. Preincubation with caspase inhibitors protectedHMA-induced apoptosis of SC2G cells. When a human bcl-2gene was transfected in SC2G cells and overexpressed, SC2G cells seemedto acquire tolerance for HMA. These data indicate that HMA-sensitivetyrosine kinase(s) can regulate apoptosis and inhibit bcl-2 expressionin SC2G mouse androgen-dependent cells. Tyrosine kinase(s) seemed to bea member of signal transduction between androgen receptor activationand bcl-2 expression.