Dog kidney (MDCK) cells are stimulated to produce prostaglandins and deacylate cellular lipids by metabolically activated polycyclic hydrocarbon carcinogens, aflatoxin B1, and epidermal growth factor. Tumor-promoting 12-O-tetradecanoylphorbol-13-acetate and phorbol-12,13-didecanoate, but not the non-tumor-promoting 4α-phorbol-12,13-didecanoate, stimulate deacylation of cellular lipids, prostaglandin biosynthesis, and morphological changes in cultured MDCK cells. The increased prostaglandin biosynthesis and these morphological changes require at least 24 hr for expression. Cycloheximide inhibits the phorbol diester-stimulated prostaglandin biosynthesis, the changes in morphology, and the increased lipid deacylation, but hydrocortisone does not. The prostaglandin synthesis stimulated by the tumor-promoting phorbol diesters is reversible.

In terms of the two-stage model of skin carcinogenesis, some of the carcinogens, epidermal growth factor and the phorbol diesters, can be acting as promoters. The tumorpromoting phorbol diesters and epidermal growth factor have been shown to inhibit differentiation, and it has been suggested that the mechanism of action of the biologically active phorbol diesters (and that of all promoters) may be related to these antidifferentiation properties. Phospholipase activity and/or arachidonic acid metabolism may be mediator(s) of cellular differentiation.


Presented at the John E. Fogarty International Center Conference on Hormones and Cancer. March 29 to 31, 1978. Bethesda, Md. Publication 1192 from the Graduate Department of Biochemistry Brandeis University. Supported by Grant HD-07966 from the National Institute of Child Health and Human Development and Grant CA-17309 from the National Cancer Institute.

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