Celecoxib increased cellular ATRA sensitivity of human colon cancer cell lines through COX-2-independent mechanisms

Retinoid resistance has limited clinical activity of retinoids as differentiation-inducing and   apoptosis-inducing drugs.  The present study was designed to investigate whether celecoxib (selective COX-2 inhibitor) has effects on cellular retinoid sensitivity of human colon cancer cell lines and its possible mechanism.  Cell viability was measured by MTT assay.  Apoptosis was detected by Annexin-V/PI staining and flow     cytometry assay.  PGE2 production was measured by ELISA assay.  Expression of RARβ was assayed by Western blotting.  The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines.  Further study showed the ATRA and   celecoxib combination induced greater apoptosis, and the addition of PGE2 did not affect the number of    apoptotic cells induced by the combination.  Moreover, NS398 (another selective COX-2 inhibitor) did not   affect the inhibitory effects of ATRA on both cell lines.  Western blotting showed that the expression of RARβ in HT-29 cell lines increased in celecoxib group and combination group.  And the addition of PGE2 did not  affect the expression of RARβ induced by celecoxib either.  In conclusion, celecoxib increased expression of RARβ and cellular ATRA sensitivity through COX-2-independent mechanisms, which may provide a potential strategy for combination therapy.