An antisense oligodeoxynucleotide that depletes RIα subunit of cyclic AMP-dependent protein kinase induces growth inhibition in human cancer cells

Enhanced expression of the RI_α subunit of cyclic AMP-dependent protein kinase type I has been correlated with cancer cell growth. We provide evidence that RI_α is a growth-inducing protein that may be essential for neoplastic cell growth. Human colon, breast, and gastric carcinoma and neuroblastoma cell lines exposed to a 21-mer human RI_α antisense phosphorothioate oligodeoxynucleotide (S-oligodeoxynucleotide) exhibited growth inhibition with no sign of cytotoxicity. Mismatched sequence (random) S-oligodeoxynucleotides of the same length exhibited no effect. The growth inhibitory effect of RI_α antisense oligomer correlated with a decrease in the RI_α mRNA and protein levels and with an increase in RII_β (the regulatory subunit of protein kinase type II) expression. The growth inhibition was abolished, however, when cells were exposed simultaneously to both RI_α and RII_β antisense S-oligodeoxynucleotides. The RII_β antisense S-oligodeoxynucleotide alone, exhibiting suppression of RII_β along with enhancement of RI_α expression, led to slight stimulation of cell growth. These results demonstrate that two isoforms of cyclic AMP receptor proteins, RI_α and RII_β, are reciprocally related in the growth control of cancer cells and that the RI_α antisense oligodeoxynucleotide, which efficiently depletes the growth stimulatory RI_α, is a powerful biological tool toward suppression of malignancy.