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Effect of Antisense Mediated BCL-2 Suppression on the Expression of the Androgen Receptor and Coactivating p300 and CREB Binding Proteins

Author(s): Marvin Rubenstein, Courtney M. P. Hollowell, and Patrick Guinan

Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models. While most oligos target growth factors or their receptors, others are directed against inhibitors of apoptosis or mediators of androgen activity. In previous experiments, mono- and bispecific oligos directed against bcl-2 suppressed both the targeted bcl-2 protein (an inhibitor of apoptosis) and non-targeted caspase-3 (a promoter of apoptosis), potentially negating the effect of therapeutic bcl-2 inhibition. Subsequently we reported that AR and p300 expression were significantly enhanced by these oligos. In a continuation of this study, we now report that the expression of another androgen receptor co-stimulatory protein, CREB binding protein (CREBBP), is not similarly increased. These data suggest that oligo treatment directed against bcl-2 can be evaded through compensatory increases in AR and p300 expression. Increased AR and p300 expression may transition the tumor to a more dedifferentiated and aggressive phenotype. However, not all co-stimulating proteins (CREBBP) are involved, and this may be important when controlling unanticipated (compensatory) effects of gene therapy.

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