Regulation of Cyclic AMP and Cyclic GMP in Morris Hepatomas and Liver

Summary

Studies on the regulation of tissue levels and action of adenosine 3′:5′-monophosphate (cyclic AMP) and cyclic guanosine 3′:5′-monophosphate (cyclic GMP) in Morris hepatomas and liver have been reviewed. Though the data is incomplete in some areas, the following generalizations can be made. A prominent difference between Morris hepatomas and normal liver, in relation to cyclic AMP formation, is the decreased responsiveness of tumor adenylyl cyclase to glucagon. This characteristic is most marked in rapidly growing hepatomas and appears to be associated with diminished plasma membrane binding of glucagon; regenerating liver and fetal liver resemble hepatomas in their responsiveness to glucagon. The responsiveness of adenylyl cyclase to epinephrine is, in contrast, generally enhanced in hepatomas as well as in regenerating and fetal liver. Marked increases in particulate guanylyl cyclase activities, relative to corresponding soluble activities, are seen consistently in Morris hepatomas and in regenerating and fetal liver; in the latter tissues, increases in plasma membrane guanylyl cyclase activities can be correlated with increased proliferative activity. Although the total cyclic AMP phosphodiesterase activities are significantly reduced in all Morris hepatomas examined, the activities of the high affinity (low Km) cyclic AMP phosphodiesterase in plasma membranes from some Morris hepatomas are higher than those of normal liver. The degradation of cyclic GMP by Morris hepatomas is also impaired, most notably in the particulate fractions. In regenerating and fetal liver the activities of cyclic AMP and cyclic GMP phosphodiesterases are, in contrast, not changed appreciably. The ratios of cyclic GMP levels, relative to cyclic AMP, tend to be higher in Morris hepatomas than in normal liver. Though these ratios are highest in rapidly growing hepatomas, the correlation between cyclic nucleotide levels and tumor growth rate is not strong. The correlation between cyclic GMP/cyclic AMP ratios and hepatocyte proliferation is controversial at this time; the most recent studies on regenerating liver suggest that these ratios are increased prior to the proliferative phase. Only a few studies have been carried out on cyclic nucleotide binding proteins and kinases. These studies indicate that: cytosols from rapidly growing hepatomas have a reduced ability to bind cyclic AMP with increased (?) binding of cyclic GMP; there is a positive correlation between cyclic AMP binding and tumor sensitivity to growth inhibition by dibutyryl cyclic AMP; cytosol fractions from rapidly growing hepatomas generally have reduced cyclic AMP dependent protein kinase activities and increased endogenous (cyclic AMP independent) kinase activities.