The regulation of protein kinase C by chenodeoxycholate, deoxycholate and several structurally related bile acids

• Published in: Carcinogenesis (New York) 1987-02, Vol.8 (2), p.217-220
• Main Authors: Fitzer, Cheryl J., O'Brian, Catherine A., Guillem, Josá G., Weinstein, I.Bernard
• Format: Article
• Language: English
• Subjects: Animals; Bile Acids and Salts - pharmacology; Biological and medical sciences; Calcium - metabolism; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Chenodeoxycholic Acid - pharmacology; Deoxycholic Acid - pharmacology; Enzyme Activation - drug effects; In Vitro Techniques; Medical sciences; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Rats; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/8.2.217

There is increasing evidence that the enzyme protein kinase C (PKC) mediates the action of phorbol ester tumor promoters and also the action of certain growth factors. The present studies indicate that the bile acids chenodeoxycholate and deoxycholate inhibit the Ca2+ (PS) dependent activity of PKC in the presence of 1 mM Ca2+, whereas seven structurally related bile acids do not detectably inhibit the enzyme under these conditions. Chenodeoxycholate and deoxycholate appear to inhibit PKC by interactions with both Ca and PS, since their inhibitory potencies are reduced at an elevated PS concentration and since both of these bile acids actually enhance PKC activity, ˜2-fold, when assayed at an elevated Ca2+ concentration (2 mM). Seven related bile acids also caused an ˜2-fold enhancement of PKC activity in the presence of 2 mM Ca2+ Chenodeoxycholate and deoxycholate also caused an ˜1.3-fold enhancement of PKC activity in the presence of 12-O-tetradecanoyl phorbol 13-acetate (FPA) and PS, and the absence of added Ca Thus, depending on the reaction conditions, specific bile acids can act directly to inhibit or enhance PKC activity. There is evidence that during colon cancer formation, both in rodents and in humans, bile acids may act as tumor promoters. Thus the mediation of tumor promotion by bile acids in vivo may involve direct activation of PKC by the bile acids them selves. The present results suggest that the relative extents of absorption of Ca2+ and bile acids by the colonic mucosa may alter the activity of PKC in the mucosa, and thus alter the growth properties of this tissue. The present studies also suggest that lipophilic anionic compounds may provide a new approach to developing therapeutic agents that act by modulating PKC.