Enzymes of cyclic 3',5'-nucleotide metabolism in human renal cortex and renal adenocarcinoma.

Enzymes of cyclic 3′,5′-nucleotide metabolism in human renal cortex and renal adenocarcinoma. Since anomalies in the metabolism of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) may be associated with neoplasias either as a cause or a consequence, we have investigated enzymes of cAMP and cGMP metabolism from normal human renal cortical tissue and from renal adenocarcinomatous tissue. Specific activities of adenylate cyclase—basal or stimulated by sodium fluoride or by 5′-guanylylimidodiphosphate—were similar in subcellular fractions from the tissues of normal cortex and adenocarcinoma. In contrast to that in cortex, adenylate cyclase in adenocarcinoma was unresponsive to parathyroid hormone, calcitonin, and vasopressin, and stimulation by prostaglandins PGE 1 and PGE2 was decreased. Adenylate cyclase from renal adenocarcinoma composed of "clear cells" was also unresponsive to glucagon (GLU) and l-isoproterenol (ISO). Adenylate cyclase from adenocarcinoma composed of "dark cells," in contrast, had higher responsiveness to GLU and ISO. In cortex, the highest specific activity of guanylate cyclase was in particulate fractions, whereas in adenocarcinoma, the specific activity of soluble guanylate cyclase was higher than that of particulate fractions and also than in cytosol from normal cortex. Guanylate cyclase in all fractions was stimulated by 1 mM azide in both cortex and adenocarcinoma. The specific activities of cAMP phosphodiesterase from subcellular fractions of clear-cell adenocarcinoma did not differ from that of cortex, whereas the specific activities of this enzyme from dark-cell tumors was markedly higher. Cyclic GMP phosphodiesterase specific activity from cytosol of clear-cell adenocarcinoma was lower than that in the cortex, but the enzyme activity in dark-cell adenocarcinoma cytosol was higher than that in cortex. These results suggest that the accumulation of lipids and glycogen in the clear-cell adenocarcinoma may be due to an unresponsiveness of tumor-cell-adenylate cyclase to GLU and β-catecholamines. Observations also suggest that changes in enzymes of cyclic 3′,5′-nucleotide metabolism may favor higher accumulation of cGMP and lower accumulation of cAMP in renal adenocarcinoma. Enzymes du metabolisme du 3′, 5′-nucleotide cyclique dans le cortex renal et l'adenocarcinome renal humain. Du fait que des anomalies du metabolisme du cAMP et du cGMP peuvent etre associees avec une neoplasie soit comme une cause soit comme une consequence, nous avons etudie les enzymes du metabolisme du cAMP et du cGMP du cortex renal et de l'adenocarcinome renal humains. Les activites specifiques de l'adenylate cyclase, basales ou stimulees par NaF ou par GPPNHP sont semblables dans les fractions subcellulaires du cortex normal et de l'adenocarcinome. A la difference de celle du cortex, l'adenylate cyclase de l'adenocarcinome ne repond pas a l'hormone parathyroidienne (PTH), a la calcitonine, et a la vasopressine; la stimulation par les prostaglandines PGE 1 et PGE 2 est moindre. L'adenylate cyclase d'adenocarcinome renal compose de cellules claires ne repond pas non plus au glucagon (GLU) et au l-isoproterenol (ISO). L'adenylate cyclase de l'adenocarcinome compose de cellules sombres, au contraire, a une reponse superieure a GLU et ISO. Dans le cortex, l'activite specifique la plus elevee de la guanylate cyclase est situee dans les fractions particulaires alors que dans l'adenocarcinome 1'activite specifique de la guanylate cyclase soluble est plus elevee que celle des fractions particulaires et que celle du cytosol du cortex normal. La guanylate cyclase de toutes ces fractions est stimulee par 1'azide 1 mM aussi bien dans le cortex que dans l'adenocarcinome. Les activites specifiques de la cAMP phosphodiesterase des fractions subcellulaires d'adenocarcinome a cellules claires ne sont pas differentes de celles du cortex, alors qu'elles sont superieures dans le cellules sombres tumorales. L'activite specifique de la cGMP phosphodiesterase est inferieure dans le cytosol d'adenocarcinome a cellules claires, par rapport a celle du cortex, mais superieure dans l'adenocarcinome a cellules sombres. Les resultats suggerent que l'accumulation de lipides et de glycogene dans les adenocarcinomes a cellules claires peut etre due a l'absence de reponse de l'adenylate cyclase des cellules tumorales a GLU et aux beta-catecholamines. Ces observations suggerent aussi que les modifications des enzymes du metabolisme du 3′,5′-nucleotide cyclique peuvent favoriser une accumulation importante de cGMP et faible de cAMP dans l'adenocarcinome renal.