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Subunit of Cyclic AMP-dependent Protein Kinase Induces Growth Inhibition in Human Cancer Cells
Cellular Biochemistry Section [H. Y., A. B., G. T., Y. S. C-C.] and Experimental Oncology Section [S. M.], Laboratory of Tumor Immunology and Biology, National Cancer Institute; and Food and Drug Administration [S. L. B.], Bethesda, Maryland 20892; Terumo Corporation [K. M.], Kanagawa, Japan
Enhanced expression of the RI
subunit of cyclic AMP-dependent protein kinase type I has been correlated with cancer cell growth. We provide evidence that RI 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 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 antisense oligomer correlated with a decrease in the RI mRNA and protein levels and with an increase in RIIß (the regulatory subunit of protein kinase type II) expression. The growth inhibition was abolished, however, when cells were exposed simultaneously to both RI and RIIß antisense S-oligodeoxynucleotides. The RIIß antisense S-oligodeoxynucleotide alone, exhibiting suppression of RIIß along with enhancement of RI expression, led to slight stimulation of cell growth. These results demonstrate that two isoforms of cyclic AMP receptor proteins, RI and RIIß, are reciprocally related in the growth control of cancer cells and that the RI antisense oligodeoxynucleotide, which efficiently depletes the growth stimulatory RI, is a powerful biological tool toward suppression of malignancy.
1 To whom correspondence should be addressed, at National Cancer Institute, National Institutes of Health, Building 10, Room 5B38, Bethesda, MD 20892.
Received 5/28/92. Accepted 12/ 8/92.
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