Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Abstract

Abstract:Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE 2 production was measured with the ELISA assay. The expression of RARβ was assayed via 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, but that the addition of PGE 2 did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARβ in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE 2 did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARβ and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.

Cell Survival Signalling through PPARδ and Arachidonic Acid Metabolites in Neuroblastoma

“…Our study, alongside others [11], [12], has shown that combining RA with celecoxib synergistically promotes cell death of neuroblastoma cells in vitro . It is likely that inhibition of AA metabolism by cyclooxygenases and lipooxygenases promotes cell death by two mechanisms: firstly by preventing the synthesis of mediators of cell survival and, secondly, by promoting an accumulation of AA [36].…”

“…Previous studies suggest that PGE2 is an important mediator of RA-induced cell survival signalling [38]–[40]. However, later studies, including this study, have shown that exogenous PGE2 does not affect ATRA and celecoxib-induced cell death [11]. Results from a range of experimental approaches support a COX2-independent mechanism for RA mediated cell survival signalling.…”

CCL28-induced RARβ expression inhibits oral squamous cell carcinoma bone invasion

“…Overexpression of RARβ induced growth arrest and apoptosis in HSC4 and HO-1-N-1 oral cancer cell lines that have very low RARβ expression and resistance to RA (60), and downregulation of RARβ blocked the growth-inhibitory effect of RA in HNSCC cells (61). In addition, induction of RARβ increased retinoid sensitivity and suppressed EMT in cancer cells (62)(63)(64). RARβ expression has been reported to be activated by a rapid demethylation of its gene promoter or the removal of HDAC1 from the RARβ gene (65,66).…”

The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells

“…These ligands are known to have different affinity for RA receptors. Specifically, RAR subtypes have a higher affinity to and become activated by ATRA than other RA ligands [ 10 , 11 ]. 9-cis RA binds to both RXR and RAR receptors but with higher affinity to RXR [ 10 ].…”