Increased expression of the androgen receptor with p300 and interleukin-6 coactivators compensate for oligonucleotide suppression of bcl-2: no increased CREB binding protein or interleukin-4 expression

摘要

Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth regulatory proteins. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. We previously evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein bcl-2. LNCaP cells adapted to this restoration of apoptosis with suppression of caspase 3 (an apoptosis promoter) and an enhanced expression of the androgen receptor (AR), suggesting an increased sensitivity to androgens. In a continuation of this study, we evaluated the expression of AR coactivators p300, its homolog CREB binding protein (CREBBP) and cytokines interleukin (IL)-4 and IL-6, finding p300 and IL-6 similarly enhanced. LNCaP cells are hormone sensitive and untreated cells express minimal p300 activity. Therefore, the enhanced expression which followed oligo treatment makes its induction more impressive and implies a pattern of gene expression more associated with later stage (androgen insensitive) disease. This suggests that oligo treatment directed against bcl-2 can be evaded through compensatory changes in AR expression and some coactivators, promoting tumor growth, and may promote transformation of the tumor to a more aggressive phenotype.