Dual mechanisms of action of the retinoid CD437: Nuclear retinoic acid receptor-mediated suppression of squamous differentiation and receptor-independent induction of apoptosis in UMSCC22B human head and neck squamous cell carcinoma cells

The synthetic retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carb oxylic acid (CD437), which can bind to and activate the nuclear retinoic ac id receptors beta and gamma (RAR beta/gamma), is a potent inducer of apopto sis in various cancer cell lines. However, this effect was reported to be i ndependent of RARs. In this study, we compared and contrasted the potencies and mechanisms of action of CD437 and several other receptor-selective ret inoids in induction of apoptosis and modulation of squamous differentiation in UMSCC22B human head and neck squamous cell carcinoma cell line. CD437 a nd the structurally related retinoid CD2325 exhibited almost equal potency in inducing apoptosis, whereas several other retinoids failed to induce apo ptosis. The RAR-specific pan antagonist AGN193109 failed to suppress CD437- induced apoptosis, indicating that the induction of apoptosis by CD437 was RAR-independent. c-Fos expression was induced by CD437 and CD2325 that indu ced apoptosis in the cell line but not by other retinoids that failed to in duce apoptosis, suggesting a role for c-Fos in CD437-induced apoptosis. At low concentration (0.01 mu M), CD437 shared with several other receptor-sel ective retinoids the ability to suppress the mRNA levels of the squamous di fferentiation markers Spr1, involucrin, and cytokeratin 1. This effect of C D437 could be blocked by AGN193109. We conclude that CD437 can exert its ef fects in UMSCC22B human human head and neck squamous cell carcinoma cells b y at least two mechanisms: RAR-mediated suppression of squamous differentia tion and RAR-independent induction of apoptosis.