Retinoids have great promise in the area of
cancer therapy and
chemoprevention. These natural and synthetic derivatives of
vitamin A have been shown to play an important role in regulating cell differentiation and proliferation. While
all-trans-retinoic acid (ATRA) has been demonstrated to inhibit the growth of several ovarian tumor cell lines, other ovarian
carcinoma cell lines have been found to be resistant to
retinoid dependent growth suppression. Interestingly, a novel synthetic
retinoid, CD437 or
AHPN, has been demonstrated to inhibit the growth of both ATRA-sensitive (CA-OV3) and ATRA-resistant (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 RXRs) in mediating cellular responses to
retinoids, we wished to determine the 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 dominant negative mutant of all RAR subtypes called
RAR-beta (R269Q), or through the 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-OV3 and SK-OV3 cells by
AHPN/CD437. Likewise, overexpression of wild type
RAR-gamma was found to increase apoptosis
after treatment with
AHPN/CD437. Our results suggest that in ovarian
carcinomas,
AHPN/CD437 induced apoptosis is mediated at least in part via an RAR pathway.