TRANSFORMATION REVERSION INDUCED IN JB6 RT101 CELLS BY AP-1 INHIBITORS

The present study was directed to characterizing the reversion of neop lastic epidermal JB6 RT101 cells by AP-1 inhibiting drugs, Treatment o f tumorigenic JB6 RT101 cells with retinoic acid (RA), fluocinolone ac etonide (FA) or forskolin (FN) induced drug dependent (reversible) rev ersion of transformation. A synergistic effect on reversion was found with the three drugs in combination. Cells reverted by these three dru gs also showed reduced levels of AP-1 transcription factor activity. A fter long term exposure of RT101 cells to FA, enrichment of hat revert ants occurred in the population while a few unreverted cells formed fo ci. These unreverted cells appeared to be FA-resistant. Cloning of cel ls following RA treatment revealed stable reversion at least 2 months after drug withdrawal, Stable revertants showed lower basal AP-1 activ ity than RT101 cells (P < 0.01) and unstable revertants returned to tr ansformed phenotype and elevated AP-1 activity within days following d rug withdrawal. To our knowledge this is the first demonstration that drug induced reversion co-selects for reduced AP-1 activity, These dat a suggest that the JB6 RT101 cell line is a useful cell model for stud ying reversion of transformation and that inhibition of AP-1 activity may be one molecular mechanism of reversion, Considering the developme nt of resistance with FA alone and the relative inefficiency of RA or FN alone, combinations of the three AP-1 activity inhibitors RA, FA an d FN may be useful for further animal and clinical studies.