Mechanisms by Which Phorbol Ester Tumor Promoters Affect Gene Expression in Human Cells

Tumor promoters were originally defined as agents that promote the neoplastic transformation of cells pretreated with a subcarcinogenic dose of an initiating carcinogen. From a large body of studies using the mouse skin model, it appears that initiating carcinogens act by inducing genetic alterations of the nuclear genome (i.e. mutations) that lead to activation of protooncogenes such as c-Ha-ras. 1 The activation of a single proto-oncogene is, however, insufficient to induce the malignant phenotype, but subsequent exposure of the initiated cells to a tumor promoter does lead to neoplastic transformation. 2 Some of the most potent tumor promoters are natural plant products that belong to the phorbol ester class, such as 12-O-tetradecanoylphorbol-13-acetate (TPA). The mechanism by which tumor promoters act, as opposed to the mechanism of initiation, has remained elusive for many years. However, several recent key observations have given us some very important clues to the possible mechanism of tumor promotion.