In LNCaP cells enhanced expression of both androgen receptor and costimulatory protein p300 compensate for antisense oligonucleotide suppression of bcl-2

摘要

Background: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. In LNCaP cells we 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 an enhanced expression of the androgen receptor (AR) suggesting an increased sensitivity to androgens. In a continuation of this study, we now evaluate the expression of p300, an AR coactivating protein expressed in the later stages of prostate cancer. Method and results: In previous experiments, monospecific and bispecific oligos directed against bcl-2 suppressed both the targeted bcl-2 protein (an inhibitor of apoptosis) and the nontargeted caspase-3 (a promoter of apoptosis), potentially negating the effect on apoptosis produced by specific inhibition of bcl-2. In a further study we reported that expression of the AR was significantly enhanced by these oligos. We now report that expression of p300 is similarly enhanced. LNCaP cells are hormone sensitive and the untreated cells expressed minimal p300 activity. Conclusions: 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 not only can be evaded through compensatory changes in AR expression which promotes tumor growth, but the induced expression of p300 may transition the tumor to a more dedifferentiated and aggressive phenotype.