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Protein Kinase A RI Antisense Inhibition of PC3M Prostate Cancer Cell Growth: Bcl-2 Hyperphosphorylation, Bax Up-Regulation, and Bad-Hypophosphorylation

Cellular Biochemistry Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1750 [Y. S. C., M-K. K., L. T., Y. S. C-C.]; Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201 [R. S.]; and Hybridon, Inc., Cambridge, Massachusetts 02139 [S. A.]

It has been shown that expression of the RI subunit of cyclic AMP (cAMP)-dependent protein kinase is enhanced in human cancer cell lines, primary tumors, and cells after transformation. Using an antisense strategy, we have shown that RI has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequence- and target-specific effects of exogenous RI antisense oligodeoxynucleotides (ODNs) and endogenous antisense gene on tumor growth, apoptosis, and cAMP signaling in androgen-insensitive prostate cancer cells, both in vitro and in nude mice. Here, we show that an RI antisense, RNA/DNA mixed backbone ODN exerts a reduction in RI expression at both the mRNA and protein levels, up-regulation of both the RIIß subunit of cAMP-dependent protein kinase or protein kinase A and c-AMP-phosphodiesterase IV expression, and inhibition of cell growth. Growth inhibition was accompanied by changes in cell morphology and the appearance of apoptotic nuclei. In addition, Bcl-2 hyperphosphorylation; increase in the proapoptotic proteins Bax, Bak, and Bad; and Bad hypophosphorylation occurred in the antisense-treated cells. These effects of exogenously supplied antisense ODN mirrored those induced by endogenous antisense gene overexpression. The RI antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RI protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RI antisense, via efficient depletion of the growth stimulatory molecule RI, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth.

Commentary

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