Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN)

Retinoic acid (RA) induces differentiation of S91 melanoma cells through ac tivation of RA receptor (RAR)gamma without affecting cell viability. The no vel RAR gamma -agonist CD437(AHPN), however, also induces concomitant apopt osis through an unknown mechanism which was investigated here. By utilizing DNA microarray analysis, five apoptosis-associated, CD437-induced transcri pts (CITs) were identified. Interestingly, all CITs are also regulated by p 53 in a DNA damage response, and consistent with this interpretation, CD437 was found to cause DNA adduct-formation. However, p53 is not required for CD437-dependent regulation of CITs. Among this set of genes, induction of p 21(WAF1/CIP1) is likely to be responsible for early S-phase growth-arrest o f CD437-treated cells, whereas ei24 is a critical mediator of CD437-induced apoptosis in S91 cells. These data suggest an RAR-independent mechanism in which CD437 causes DNA adduct-formation, resulting in induction of a p53-i ndependent DNA damage response, and subsequent growth-arrest and apoptosis. CD437-mediated DNA adduct-formation may also explain its apoptotic effects in other cell types.