DOWN-REGULATION OF PROTEIN-KINASE-C ACTIVITY IN 1,2-DIMETHYLHYDRAZINE-INDUCED RAT COLONIC TUMORS

Recent studies by our laboratory have indicated that alterations in protein kinase C activity may be involved in the early stage(s) of malignant transformation in the 1,2-dimethylhydrazine model of colonic adenocarcinoma. In order to further evaluate the possible role of protein kinase C in this multistage process, rats were given subcutaneous weekly injections of this procarcinogen (20 mg/kg body weight) or diluent for 26 weeks. One week after receiving the last injection, animals were killed and control colonic tissue, tumor tissue and tissue at least 1 cm away from these tumors ('uninvolved mucosa') were harvested. The activity and distribution of protein kinase C in the cytosolic and membrane fractions of these preparations as well as their 1,2-diacylglycerol mass were then examined and compared. The results of these studies demonstrated that: (1) total protein kinase C activity was reduced by approximately 35% and 60%, respectively, in the 'uninvolved' colonic mucosa and tumors of carcinogen-treated rats compared to their control counterpart values; (2) in the 'uninvolved' mucosa, this decrease in total activity was secondary to a decrease solely in cytosolic protein kinase C, whereas, in tumors both membrane and cytosolic activities were reduced; and (3) 1,2-diacylglycerol mass was significantly increased in colonic tumors versus control values. Based on these findings, it would appear that alternations in the cellular distribution and total activity of protein kinase C, possibly secondary to increases in 1,2-diacylglycerol mass, may also play a role in the latter stage(s) of malignant transformation in this experimental model.