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Promoter-induced cellular responses closely correlated with the enhancement of cell transformation
Abstract:
In order to understand the mechanisms of tumor promotion, the relationship between the early effects induced by promoters and the enhancement of transformation was investigated using transformable, promoter-sensitive mouse clone Balb/3T3 A31-1-1. Emphasis was placed on the measurement of all parameters in the same clonal line under the same conditions. The potentials of various derivatives of phorbol ester, indole alkaloid, and polyacetate for enhancing transformation in 3-methylcholanthrene-initiated cells were, in general, in parallel with their potentials for inhibiting phorbol-12, 13-dibutyrate-binding and for inducing early responses such as the reduction of epidermal growth factor (EGF)-binding to cell surface receptors, the increase in glucose uptake and release of arachidonic acid, and the stimulation of DNA synthesis in cells arrested at G0. There was an exception to this general rule; some agents, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and debromoaplysiatoxin, showed very strong activities to induce most of the early responses, whereas they showed slight or no activity to enhance cell transformation. The cause of this exception was ascribed to their higher susceptibility to metabolic or physical inactivation. However, we found that the continuous suppression of EGF-binding to cell surface receptors by promoters was well correlated with the enhancement of transformation, without exception. Furthermore, continuous elevation or reduction of the number of EGF receptors by various hormones was associated with the suppression or enhancement of cell transformation. The hypothesis was proposed that a continuous decrease in the number of EGF-receptors on the cell surface, or its underlying mechanisms, plays an important role in the enhancement of transformation. The mechanisms by which activation of protein kinase C leads to the enhancement of transformation were discussed, with emphasis on cytoskeletal alteration.