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Synergistic Inhibition of Phorbol Ester-induced Transformation of JB6 Cells by Transforming Growth Factor-ß and Retinoic Acid¹

Laboratory of Molecular Immunoregulation, Biological Response Modifiers Program [L. F., F. W. R., J. J. O.]; Biological Carcinogenesis and Development Program, Program Resources, Inc./DynCorp [F. D., C. R. F.]; and Laboratory of Viral Carcinogenesis [N. H. C.], National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Transforming growth factor-ß (TGF-ß) 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-ß, 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 non-tumorigenic and anchorage-dependent JB6 cells acquired a tumor phenotype, as shown by the acquisition of tumorigenicity and anchorage independence. We found that TGB-ß inhibited the PMA-induced transformation of a subclone of JB6 cells. The effect of TGF-ß was due to an anti-transformation promoting activity, rather than to generalized growth inhibition, since TGF-ß 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-ß was synergistic with retinoic acid, a known anti-tumor promoter, in inhibiting the PMA-induced transformation of JB6 cells. Examination of TGF-ß receptor expression on JB6 cells, by both binding and affinity labeling, showed that treatment with PMA significantly decreased TGF-ß receptor expression while retinoic acid counteracted this effect of PMA, thus suggesting that the synergy between retinoic acid and TGF-ß may be due, at least in part, to modulation of TGF-ß receptor expression. TGF-ß, therefore, appears to function as an incomplete antipromoter whose action can be permitted and/or complemented by retinoic acid. Our data demonstrating that TGF-ß has anti-transformation promoting activity suggest that TGF-ß 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 maligant transformation.

¹ This project has been funded at least in part with Federal funds from the Department of Health and Human Services under contract number N01-C0-74102 with Program Resources, Inc. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

² Present address: Clinica Pediatrica, IRCCS Pol. S. Matteo, 27100 Pavia, Italy.

³ Mailing address: Sterling Research Group, Sterling Drug, Inc., 25 Great Valley Parkway, Malvern, PA 19355.

⁴ To whom requests for reprints should be addressed at Laboratory of Molecular Immunoregulation, Biological Response Modifiers Program, National Cancer Institute-Frederick Cancer Research and Development Center, Building 560, Room 21-89A, P. O. Box B, Frederick, MD 21702-1201.

Received 10/ 2/89. Accepted 11/28/90.

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