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1,2-Dimethylhydrazine-induced Alterations in Protein Kinase C Activity in the Rat Preneoplastic Colon¹

Department of Medicine, University of Chicago Hospitals and Clinics, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637

Recently, a number of studies in experimental animals and humans have suggested that alterations in the activity of protein kinase C (PKC) may be involved in the malignant transformation process. To determine whether such alterations in this kinase were present before the development of 1,2-dimethylhydrazine (DMH)-induced colon cancers, rats were given s.c. injections of this procarcinogen (20 mg/kg body weight/week) or diluent for 10 or 15 weeks. Animals were sacrificed after these time periods and colonic epithelium was harvested from each group. The activity and distribution of PKC in the cytosolic and membrane fractions of these preparations as well as 1,2-diacylglycerol mass and phosphoinositide turnover were then examined and compared in the presence and absence of 10 nM 1,25-dihydroxycholecalciferol, an agent which has previously been found to influence these biochemical parameters in the normal rat colonic epithelium.

The results of these studies demonstrate that: (a) the percentage of PKC activity in the membrane fraction was significantly greater in DMH-treated animals compared to their control counterparts at 10 and 15 weeks; (b) the total PKC activity was similar at 10 weeks, but markedly reduced in the colonic mucosa of the DMH-treated group at 15 weeks; (c) 1,2-diacylglycerol mass and phosphoinositide turnover were increased in the colonic mucosa of rats administered this carcinogen at both time points; and (d) in control, but not in DMH-treated animals, in vitro addition of 1,25-dihydroxycholecalciferol increased PKC activity, 1,2-diacylglycerol mass and phosphoinositide turnover at each of the times studied. Based on these findings, it would appear that alterations in PKC activity may play a role in the malignant transformation process of the colon in animals administered DMH.

¹ These experiments were supported by the Samuel Freedman Laboratories for Cancer Research Fund as well as by USPHS Grant CA 36745 awarded by the National Cancer Institute, by USPHS Grant DK 26678 (Clinical Nutrition Research Unit) awarded by the National Institute of Diabetes and Digestive and Kidney Diseases, Department of Health and Human Services, and by USPHS Grant DK 39573 by the National Institute of Diabetes and Digestive and Kidney Diseases, Department of Health and Human Services.

² Recipient of a MERIT award from the National Cancer Institute, NIH. To whom requests for reprints should be addressed, at University of Chicago Hospitals and Clinics, 5841 S. Maryland Avenue, Box 400, Chicago, IL 60637.

Received 11/17/89. Revised 3/13/90.

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