Somatostatin inhibits colon cancer cell growth through cyclooxygenase-2 downregulation

Background and purpose: Cyclooxygenase-2 (COX-2) is expressed in colonic neoplasms, where it supports cell proliferation via prostaglandin E2 (PGE2) production. This study investigated the effects of somatostatin-14 on COX-2 expression, PGE2 production and proliferation in colon cancer cells. Experimental approach: Human colon adenocarcinoma cell lines Caco-2, HT-29 and HCT116 were used. The following techniques were employed: colourimetric assay for cell growth; 5-bromo-2′-deoxyuridine assay for DNA synthesis; enzyme immunoassay for PGE2; COX-2 mRNA silencing; RT–PCR or Western blot for somatostatin receptor subtypes, cyclooxygenase isoforms, phosphorylated-ERK-1/ERK-2 and phosphorylated-Akt. Key results: HT-29 and Caco-2 cells expressed COX-2 and somatostatin receptors (sst3/4/5 and sst3/5, respectively). HCT116 cells did express somatostatin receptors (sst2/3/5), but not COX-2. Somatostatin-14 inhibited basal COX-2 expression, PGE2 production, DNA synthesis and growth in Caco-2 cells and these effects were prevented by BN81658 (sst3 receptor antagonist). Basal proliferation of HT-29, HCT116 and COX-2-silenced Caco-2 cells was not affected by somatostatin-14. Stimulation of HT-29 cells with gastrin-17 elicited increments of ERK-1/ERK-2 and Akt phosphorylation, COX-2 expression, PGE2 production, DNA synthesis and cell growth, which were all counteracted by somatostatin-14. Somatostatin-14-induced inhibition of COX-2 expression, PGE2 production and DNA synthesis were blocked by BIM23056 (sst5 receptor antagonist). Conclusions and implications: Somatostatin decreases COX-2 expression and function in colon cancer cells via activation of sst3 or sst5 receptors, and these effects contribute to the inhibitory action of somatostatin on cell proliferation. These findings can be relevant to the development of therapeutic strategies based on the modulation of the COX-2 pathway. British Journal of Pharmacology (2008) 155, 198–209; doi:10.1038/bjp.2008.268; published online 30 June 2008