Induction of Fas expression and augmentation of Fas/Fas ligand-mediated apoptosis by the synthetic retinoid CD437 in human lung cancer cells

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-nathalene carb oxylic acid (CD437) induces apoptosis in a variety of cancer cells. Recentl y, we demonstrated that CD437 induces apoptosis in human non-small cell lun g cancer (NSCLC) cells expressing wild-type p53 by increasing the level of the death domain-containing cell surface receptor Killer/DR5. In the presen t study, we investigated whether CD437 induced the expression of Fas (CD95/ APO-1), a cell surface protein belonging to the tumor necrosis factor recep tor superfamily, which induces apoptosis upon interaction with Fas ligand ( FasL) or agonistic antibodies. We found that CD437 increased the level of F as mRNA in a time- and concentration-dependent manner in NSCLC H460 cells. The increased Fas expression was also identified at the protein level. CD43 7 induced Fas expression in three NSCLC cell lines with wild-type p53 but n ot in six NSCLC cell lines containing mutant p53, Moreover, enhanced degrad ation of wild-type p53 protein in NSCLC cells expressing human papillomavir us-16 E6 oncoprotein blocked CD437-induced Fas expression. These results im plicate the involvement of wild-type p53 in CD437-induced Fas expression in human NSCLC cells. CD437 did not change Fas mRNA stability, and actinomyci n D abolished CD437-induced expression of Fas mRNA, suggesting that CD437 i nduces Fas expression at the transcriptional level. The combination of CD43 7 and FasL or CD437 and agonistic anti-Fas antibody caused synergistic indu ction of apoptosis, Furthermore, CD437 augmented Fas/ Fast-induced apoptosi s in cell lines with wild-type p53 but not in cell lines having mutant p53, indicating that a p53-dependent mechanism is also involved in this effect. Taken together, these results demonstrate that increased Fas expression ma y play an important role in CD437-induced, p53-dependent apoptosis in human NSCLC cells.