OVEREXPRESSION OF BOTH RAR AND RXR RESTORES AP-1 REPRESSION IN OVARIAN ADENOCARCINOMA CELLS RESISTANT TO RETINOIC ACID-DEPENDENT GROWTH-INHIBITION

Retinoids including retinoic acid (RA) have been demonstrated to be ef fective growth inhibitors of a number of human cancer cell lines inclu ding ovarian adenocarcinoma cells, To begin to determine the mechanism of action by which RA inhibits the growth of ovarian carcinoma cells, we have examined AP-1 activity in two representative cell lines: CaOV -3 a RA-sensitive cell line and SK-OV-3 a RA-resistant cell line, AP-1 activity was found to be inhibited by 50% upon RA treatment of the RA -sensitive cells while there was no change in AP-1 activity following RA treatment of the RA-resistant cells, Maximal inhibition of AP-1 act ivity could be achieved in the RA-resistant SK-OV-3 cells by overexpre ssion of any one of the three retinoic acid receptor (RAR) subtypes in conjunction with retinoid X receptor (RXR) alpha. This inhibition of AP-1 activity was nearly comparable to that of the RA-sensitive cells, A similar change in AP-1 complex formation in vitro has also been obs erved, These results suggest that one mechanism by which RA inhibits g rowth of RA-sensitive ovarian carcinoma cells is by repressing AP-1 ac tivity, Moreover, in the RA-resistant cells the RAR/RXR signalling pat hway leading to inhibition of AP-1 activity is impaired however overex pression of one of the RAR subtypes along with RXR alpha is sufficient to restore this pathway.