Induction of apoptosis in ovarian carcinoma cells by AHPN/CD437 is mediated by retinoic acid receptors

Retinoids have great promise in the area of cancer therapy and chemoprevent ion. These natural and synthetic derivatives of vitamin A have been shown t o play an important role in regulating cell differentiation and proliferati on. While all-trans-retinoic acid (ATRA) has been demonstrated to inhibit t he growth of several ovarian tumor cell lines, other ovarian carcinoma cell lines have been found to be resistant to retinoid dependent growth suppres sion. Interestingly, a novel synthetic retinoid, CD437 or AHPN, has been de monstrated to inhibit the growth of both ATRA-sensitive (CA-OV3) and ATRA-r esistant (SK-OV3) ovarian tumor cell lines as well as to induce apoptosis. The overall goal of this research was to understand the mechanism by which AHPN/CD437 induces apoptosis in ovarian tumor cell lines. Since a number of studies have demonstrated the importance of nuclear receptors (RARs and RX Rs) in mediating cellular responses to retinoids, we wished to determine th e role of RARs in mediating the AHPN/CD437 response. We modulated RAR level and function by overexpressing either wild type RAR-gamma or a pan dominan t negative mutant of all RAR subtypes called RAR-beta (R269Q), or through t he use of an RAR-gamma antagonist, MM11253. We found that inhibition of RAR function reduced but did not eliminate induction of apoptosis in both CA-O V3 and SK-OV3 cells by AHPN/CD437. Likewise, overexpression of wild type RA R-gamma was round to increase apoptosis after treatment with AHPN/CD437. Ou r results suggest that in ovarian carcinomas, AHPN/CD437 induced apoptosis is mediated at least in part via an RAR pathway, (C) 2000 Wiley-Liss, Inc.