Synergistic inhibition of phorbol ester-induced transformation of JB6 cells by transforming growth factor-beta and retinoic acid.

Transforming growth factor-beta (TGF-beta) plays a complex role as a regulator of proliferation and differentiation of many cell types, including cells of epithelial origin. In this study, we examined whether TGF-beta, alone or in combination with retinoic acid, was able to inhibit the transformation of the murine epidermal cell line JB6. When treated with phorbol myristate acetate (PMA) and other tumor promoters, the nontumorigenic and anchorage-dependent JB6 cells acquired a tumor phenotype, as shown by the acquisition of tumorigenicity and anchorage independence. We found that TGB-beta inhibited the PMA-induced transformation of a subclone of JB6 cells. The effect of TGF-beta was due to an anti-transformation promoting activity, rather than to generalized growth inhibition, since TGF-beta neither inhibited the growth of monolayer cultures of JB6 cells, nor affected the colony-forming efficiency in agar of the JB6-derived permanently transformed RT101 cell line. TGF-beta was synergistic with retinoic acid, a known anti-tumor promoter, in inhibiting the PMA-induced transformation of JB6 cells. Examination of TGF-beta receptor expression on JB6 cells, by both binding and affinity labeling, showed that treatment with PMA significantly decreased TGF-beta receptor expression while retinoic acid counteracted this effect of PMA, thus suggesting that the synergy between retinoic acid and TGF-beta may be due, at least in part, to modulation of TGF-beta receptor expression. TGF-beta, therefore, appears to function as an incomplete antipromoter whose action can be permitted and/or complemented by retinoic acid. Our data demonstrating that TGF-beta has anti-transformation promoting activity suggest that TGF-beta plays a role in maintaining homeostasis of epithelial cells, not only by regulating cell proliferation and differentiation, but also by counteracting events that lead to malignant transformation.