Critical role of both retinoid nuclear receptors and retinoid-X-receptors in mediating growth inhibition of ovarian cancer cells by all-trans retinoic acid

Retinoids have been shown to inhibit the growth of a number of human tumor cells, including several ovarian adenocarcinoma cell lines. All-trams retin oic acid (RA) is an effective growth suppressor of CA-OV3 cells but not SK- OV3 cells. Since the effects of RA are known to be mediated via the nuclear receptors (RARs and RXRs), we initially compared levels of the various RAR s and RXRs in the CA-OV3 and SK-OV3 cell lines. The RA resistant SK-OV3 cel ls expressed reduced levels of RAR-alpha and RXR-alpha. Furthermore, induct ion of RAR-alpha by RA was impaired in the RA resistant SK-OV3 cells as was RARE binding and RARE-dependent transcriptional activity. These results su ggested that changes in the amounts and/or activity of RARs and/or RXR-alph a could determine the growth response of ovarian tumor cells to RA. This wa s confirmed by modulating the levels of RARs and RXR-alpha in the SK-OV3 ce lls using the LacSwitch(TM) inducible expression system. Stably transfected clones of RA resistant SK-OV3 cells exhibited a significant inhibition of growth by RA treatment when RAR-alpha was induced. Overexpression of both R AR-alpha and RXR-alpha resulted in a level of growth inhibition nearly equa l to that exhibited by the RA sensitive CA-OV3 cell line. Similar results w ere obtained when a combination of RXR-alpha and either RAR-beta or RAR-gam ma was overexpressed in SK-OV3 cells. Our results show that the nuclear rec eptors and RXR-alpha play a critical role in mediating growth suppression b y RA in ovarian cancer cells.