Somatostatin inhibits colon cancer cell growth through cyclooxygenase-2 downregulation.
OBJECTIVE
Cyclooxygenase-2 (COX-2) is expressed in colonic neoplasms, where it supports cell proliferation via prostaglandin E(2) (PGE(2)) production. This study investigated the effects of somatostatin-14 on COX-2 expression, PGE(2) production and proliferation in colon cancer cells.


METHODS
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 PGE(2); COX-2 mRNA silencing; RT-PCR or Western blot for somatostatin receptor subtypes, cyclooxygenase isoforms, phosphorylated-ERK-1/ERK-2 and phosphorylated-Akt.


RESULTS
HT-29 and Caco-2 cells expressed COX-2 and somatostatin receptors (sst(3/4/5) and sst(3/5), respectively). HCT116 cells did express somatostatin receptors (sst(2/3/5)), but not COX-2. Somatostatin-14 inhibited basal COX-2 expression, PGE(2) production, DNA synthesis and growth in Caco-2 cells and these effects were prevented by BN81658 (sst(3) 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, PGE(2) production, DNA synthesis and cell growth, which were all counteracted by somatostatin-14. Somatostatin-14-induced inhibition of COX-2 expression, PGE(2) production and DNA synthesis were blocked by BIM23056 (sst(5) receptor antagonist).


CONCLUSIONS
Somatostatin decreases COX-2 expression and function in colon cancer cells via activation of sst(3) or sst(5) 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.
Colucci
R
R
Department of Internal Medicine, University of Pisa, Pisa, Italy.
Blandizzi
C
C
Ghisu
N
N
Florio
T
T
Del Tacca
M
M
D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects*; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005755:Gastrins / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology*
C091737:BIM 23056; D052246:Cyclooxygenase 2 Inhibitors; D005755:Gastrins; D009842:Oligopeptides; D013004:Somatostatin; C013550:gastrin 17; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D017027:Protein Tyrosine Phosphatases