Antitumor Effect of Retinoic Acid Receptor-β2 Associated with Suppression of Cyclooxygenase-2

Retinoic acid receptor-beta(2) (RAR-beta(2)) is a putative tumor suppressor gene in various cancers. To determine the underlying molecular mechanisms, we transfected RAR-beta(2) cDNA into esophageal cancer TE-1 and TE-8 cells and found that RAR-beta(2) suppressed tumor cell growth in vitro and tumor formation in nude mice in TE-8 cells, whereas the stable transfection of RAR-beta(2) did not restore retinoid sensitivity or inhibit tumor formation in nude mouse in TE-1 cells. Molecularly, we revealed that RAR-beta(2) antitumor activity was associated with expression and suppression of cyclooxygenase-2 ( COX-2) in these tumor cell lines. Moreover, antisense RAR-beta(2) cDNA induced COX-2 expression in TE-3 cells. Furthermore, when COX-2 expression is first blocked by using antisense COX-2 expression vector, the effect of RAR-beta(2) is diminished in these tumor cells. In addition, we analyzed expression of RAR-beta(2) and COX-2 mRNA in tissue specimens and found that RAR-beta(2) expression is associated with low levels of COX-2 expression in esophageal cancer tissues. Induction of RAR-beta(2) expression in oral leukoplakia tissues after the patients treated with 13-cis RA correlated with a reduction in COX-2 expression and clinical response. Our findings indicate that some of RAR-beta(2) antitumor activities are mediated by suppression of COX-2 expression in some of these esophageal cancer cells. After correlating antitumor effect of RAR-beta(2) with COX-2 expression in the published studies, we also found the association. Thus, further studies will determine whether manipulation of COX-2 expression in different cancers can antagonize RAR-beta(2) activity.