Somatostatin modulates both cyclooxygenase-2 expression and proliferation in human colon cancer cells

introduction. Among cyclooxygenase isoforms, COX-1 and COX-2, the latter is sigmficantly implicated in colorectal tumongenesis and cell proliferation. By contrast, somatostatin (SST) may negatively modulate colon cancer growth. This study investigates the effects of SST on COX-2 expression and proliferation in colon cancer cells, either under basal conditions or upon stimulation with gastrin-17 (G-17). Methods. Experiments were performed on human colon adenocarcinoma cell line HT29. Reverse transcription-polymerase chain reaction (RTPCR) was used to assess mRNA expression of gastrin CCK-2 receptors, SST receptors (SSTR from 1 to 5), COX-1 and COX-2. Phosphorylation of MAP-kinase as well as COX-1 and COX-2 protein expression were determined by westem blot analysis. Cell proliferative activity was estimated by direct cell count. Results. RT-PCR revealed the expression of CCK-2 receptors, SSTR-3, SSTR-4, SSTR-5, COX-1 and COX-2 transcripts under basal conditions. COX-1 and COX-2 protein expression was confirmed by western blot. SST (0.1-100 nM) significantly decreased the basal growth rate in HT29 cells (-41.3% at 1 riM), and concentration-dependently inhibited the proliferative effects exerted by G-17 0.1 ~M (-55.2% at 1 nM). Western blot assay showed that COX-2, but not COX-l, expression was significantly enhanced by G-17. This stimulant action was prevented upon incubation of HT29 cells with PD-98059 (1-100 nM) or wortmannin (10-50 p,M), acting as inhihitors of MAP-kinase and PI3-kinase, respectively. SST reduced COX-2, but not COX-I, expression under basal conditions as well as after stimulation with G-17. Likewise, G-17 exerted a stimulant effect on MAP-kinase phosphorylation, which was fully counteracted by SST in a concentrationdependent manner. Conclusions. 1) SST can downregulate the expression of COX-2 in colon cancer cells, and such inhibitory effect may account for the antiproliferative action of this gastrointestinal peptide; 2) in colon cancer cells COX-2 expression is positively regulated by mitogenic transduction signals and this mechanism can be counteracted by inhibitory pathways induced by SST.