OVEREXPRESSION OF THE RI-ALPHA SUBUNIT OF PROTEIN-KINASE-A CONFERS HYPERSENSITIVITY TO TOPOISOMERASE-II INHIBITORS AND 8-CHLORO-CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE IN CHINESE-HAMSTER OVARY CELLS

We have shown that a mutant derivative of Chinese hamster ovary CHO-K1 cells, ADR-5, which shows hypersensitivity to topoisomerase II (topo II)-inhibitory drugs, is cross-sensitive to the site-selective cyclic AMP analogue 8-chloro-cyclic AMP. We tested the hypothesis that overex pression of the type I alpha regulatory subunit of protein kinase A ma y represent a common element conferring hypersensitivity to both topo II inhibitors and 8-chloro-cyclic AMP in ADR-5 cells. We have demonstr ated that ADR-5 cells overexpress RI alpha protein, compared to parent al CHO-K1 cells. Moreover, retroviral vector-mediated transfer of the RI alpha gene into CHO-K1 cells was able to confer a drug-hypersensiti ve phenotype similar to that exhibited by ADR-5 cells. Analysis of top o II protein levels and activity revealed no differences between paren tal and infected cells, suggesting that protein kinase A may be involv ed in the downstream processing of topo II-mediated events.