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

Abstract

Retinoids have been shown to inhibit the growth of a number of human tumor cells, including several ovarian adenocarcinoma cell lines. All-trans retinoic 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 RARs and RXRs in the CA-OV3 and SK-OV3 cell lines. The RA resistant SK-OV3 cells expressed reduced levels of RAR-α and RXR-α. Furthermore, induction of RAR-α by RA was impaired in the RA resistant SK-OV3 cells as was RARE binding and RARE-dependent transcriptional activity. These results suggested that changes in the amounts and/or activity of RARs and/or RXR-α could determine the growth response of ovarian tumor cells to RA. This was confirmed by modulating the levels of RARs and RXR-α in the SK-OV3 cells 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-α was induced. Overexpression of both RAR-α and RXR-α resulted in a level of growth inhibition nearly equal to that exhibited by the RA sensitive CA-OV3 cell line. Similar results were obtained when a combination of RXR-α and either RAR-β or RAR-γ was overexpressed in SK-OV3 cells. Our results show that the nuclear receptors and RXR-α play a critical role in mediating growth suppression by RA in ovarian cancer cells.