ABSTRACT
Claims about molecular mechanisms underlying the resistance to anti-hormones of prostate cancer cells find support in biological experiments, which involve hormone-independent activation of the androgen receptor's (AR) transcriptional activity. In order to test this hypothesis, we attempted to shut down the expression of AR by the means of target-directed antisense oligonucleotides. A set of 49 oligonucleotides matching sequences of the AR mRNA either in the coding sequence or in the 3' and 5' untranslated regions were synthesized and examined in a cellular AR-dependent reporter system. Five antisense oligonucleotides were identified as highly potent inhibitors of AR-driven gene expression in a cellular reporter assay. These five were further profiled using point-mutated control sequences for the assessment of AR inhibition. In addition the expression of another AR-driven gene, the modulator of PSA expression (gene for inhibition of prostate specific antigen, an endogenous, AR-driven gene) was examined. Finally, we observed that the hormone-independent but AR-mediated transactivation by IGF-1 could also be specifically shut-down by these antisense oligonucleotides. The selection of highly target-restricted antisense oligonucleotides in the prostate cancer cell line LNCaP provided tools to study a central role of the androgen receptor in growth regulation of prostatic cancer cell lines and could be of utility in cancer situations in vivo.
