REVERSE RELATIONSHIP BETWEEN MALIGNANCY AND CYCLIC-AMP-DEPENDENT PROTEIN-KINASE ACTIVITY IN YOSHIDA RAT ASCITES HEPATOMAS

Rat ascites hepatoma (AH) cells (10(6) cells/head) inoculated intraper itoneally into rats had host-killing ability (malignancy) in the order AH66F > AH44 > AH13 > AH7974 > AH109A > AH66 > AH130. The life span o f the rats after inoculation closely correlated with the activity of c yclic AMP-dependent protein kinase (protein kinase A) in the tumor cel ls but not the activity of Ca2+/phospholipid-dependent protein kinase (protein kinase C). hlorophenyl)-1-methyl-2-propenyl]amino]ethyl]-5-is oquinolinesulfonamide (H-87), a potent, selective inhibitor of protei n kinase A, inhibited in vitro growth of these hepatoma cells with a s imilar potency and, intraperitoneally injected, prolonged the lives of rats bearing less malignant AH66 cells (with high protein kinase A ac tivity) but did not affect the life span of rats bearing highly malign ant AH66F cells (with low protein kinase A activity). On the other han d N-(2-methylpiperazyl)-5-isoquinolinesulfonamide (H-7), an inhibitor of protein kinase C, inhibited AH66F cells more than AH66 cells, but d id not influence the life span of rats bearing either hepatoma. From t hese results it is deduced that protein kinase A may be important in t he regulation of malignancy and in vivo proliferation of AH cells.