Retinoids are a group of natural derivatives and synthetic analogs of vitamin A that are required for essential life processes. Many laboratories including our own have shown that retinoids inhibit the growth of a wide variety of tumor cells both in vivo and in vitro. Previous studies from our laboratory have investigated the effect of all-trans-retinoic acid (IRA) on the growth of ovarian carcinoma cells. The growth of the cell line CA-OV3 was found to be inhibited by RA treatment while the growth of SK-OV3 cells was not. Moreover, we showed that RA treatment blocked cell cycle progression during G-1. More recently we set out to identify potential cell cycle gene targets which mediate retinoid dependent growth suppression of ovarian carcinoma cells. Since retinoid inhibited cells are blocked in G-1 we compared the expression and activity of cell cycle genes known to function in the RB pathway in RA sensitive CA-OV3 cells and IRA resistant SK-OV3 cells. IRA treatment of CA-OV3 cells resulted in a significant enhancement in the levels of RB-2/p130 and p27kip1 protein. No comparable increase in RB-2/p130 or p27kip1 was observed in RA treated SK-OV3 cells which are not growth inhibited. Based on these studies we hypothesize that RB-2/p130 and p27 kip1 represent important molecular targets which mediate ovarian carcinoma cell growth suppression by RA. In this application we propose to better understand the mechanism of RB-2/p130 and p27 kip1 protein accumulation by retinoids and thus elucidate the molecular events required for growth arrest mediated by RA. It should be noted that the targeting of RB-2/p130 in ovarian tumor cells as an essential mediator of growth suppression by retinoids is UNIQUE in that all other tumor models exhibit only dephosphorylation of RB and not increased expression of RB-2/p130 upon treatment with retinoids. Clearly the mechanism of retinoid action in ovarian tumor cells is different from that in other models. Thus, study of the mechanism of retinoid inhibition of growth will provide valuable, important information not only on how this potential new chemotherapeutic agent may work but also on the molecular nature of growth regulation in ovarian tumor cells.
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