Abstract
e13532 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. To evaluate the specificity of this type of gene therapy, targeted and non-targeted genes were evaluated for their expression. The purpose was to identify whether additional (non-targeted) genes altered their expression in a manner which could circumvent or compensate for the suppression of bcl-2, promoting growth through increased androgen sensitivity. Methods: LNCaP prostate cells were treated with mono- and bispecific oligos directed against bcl-2. Employing RT-PCR the expression of both targeted and non-targeted genes (androgen receptor [AR], coactivators p300 and creb binding protein [CREB]) was determined. Results: LNCaP cells adapted to the suppression of bcl-2 (an apoptosis inhibitor) with enhanced expression of both AR and p300. This suggests an increased sensitivity to androgens. Conclusions: In this model, oligo treatment directed against bcl-2, may be evaded through a compensatory increase in both AR and p300 expression. This promotion of tumor growth, and the altered expression of AR coactivators normally seen in advanced disease, suggests a tumor transition to a more aggressive phenotype following suppressive treatment directed against bcl-2.
Published Version
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