Compensatory and non-compensatory effects on protein expression following BCL-2 suppression by antisense oligonucleotides.

Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth regulatory proteins. In LNCaP cells, we evaluated both monospecific and bispecific oligos that targeted and comparably suppressed the expression of bcl-2, an apoptosis inhibitory protein. Cells compensated with both suppressed caspase-3 (an apoptosis promoter) activity, and an enhancement of both androgen receptor (AR) and p300 expression. This suggests that a progression to increased androgen sensitivity accompanies bcl-2 suppression, in this tumor line. To further evaluate mechanisms of adaptation, we now evaluate the effects upon the expression of insulin-like growth factor (IGF1) and another AR coactivator, IL-4, thought to increase prostate cancer growth. IGF1 expression was not significantly altered suggesting this pathway need not be regulated when bcl-2 directed gene therapy is employed. In contrast to increased AR and p300 expression that compensated for bcl-2 suppression, the AR coactivator IL-4 expression was not increased, suggesting no role in any increased androgen sensitivity.