Inhibition by retinoids of platelet growth factor-dependent stimulation of DNA synthesis and cell division in density-arrested C3H 10T1/2 fibroblasts

The inhibition of neoplastic transformation by vitamin A and its natural and synthetic analogues, collectively called retinoids, is accomplished by an as yet unknown mechanism. In a recent report, the morphological transformation of carcinogen-treated C3H 10T1/2 fibroblasts to focus-forming transformed cells was shown to be a postconfluence event induced in density-arrested initiated cells by platelet growth factors in serum and was correlated with the mitogenic response of the preneoplastic cells to these polypeptides. The current study investigates the possibility that the inhibition of neoplastic transformation by retinoids is accomplished by blocking the mitogenic response of initiated cells to these growth factors. The results demonstrate that the stimulation by serum of DNA synthesis and cell division in normal and carcinogen-treated C3H 10T 1/2 fibroblasts after density-dependent growth arrest is inhibited in a dose-dependent manner by retinyl acetate, all-trans retinoic acid, and 4-hydroxyphenyl-retinamide over the same dose range and to the same extent that neoplastic transformation is inhibited by these retinoids. Cellular mitogenic processes sensitive to retinoid inhibition were shown to be induced specifically by platelet growth factors, rather than plasma growth factors, to occur within approximately 2 h of growth factor treatment, and to be common to cell division stimulated in density-arrested normal and initiated cells by highly purified platelet-derived or epidermal growth factor. These data suggest that the inhibition of neoplastic transformation by retinoids is accomplished by blocking the G0 to G1 transition in the mitotic response of initiated cells to platelet growth factors which act as endogenous promoters of transformation.