PMID- 23010081 OWN - NLM STAT- MEDLINE DCOM- 20130110 LR - 20181202 IS - 1872-7980 (Electronic) IS - 0304-3835 (Linking) VI - 328 IP - 1 DP - 2013 Jan 1 TI - Celecoxib induces proliferation and Amphiregulin production in colon subepithelial myofibroblasts, activating erk1-2 signaling in synergy with EGFR. PG - 73-82 LID - S0304-3835(12)00545-9 [pii] LID - 10.1016/j.canlet.2012.09.008 [doi] AB - The COX-2 inhibitor Celecoxib, tested in phase III trials for the prevention of sporadic colon adenomas, reduced the appearance of new adenomas, but was unable to affect the incidence of colon cancer. Moreover the 5years follow-up showed that patients discontinuing Celecoxib treatment had an increased incidence of adenomas as compared to the placebo arm. In the APC(min/+) mouse model short term treatment with Celecoxib reduced gut adenomas, but a prolonged administration of the drug induced fibroblast activation and intestinal fibrosis with a final tumor burden. The way Celecoxib could directly activate human colon myofibroblasts (MF) has not yet been investigated. We found that MF are activated by non toxic doses of Celecoxib. Celecoxib induces erk1-2 and Akt phosphorylation within 5'. This short term activation is apparently insufficient to cause phenotypic changes, but the contemporary triggering of EGFR causes an impressive synergic effect inducing MF proliferation and the neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist involved in colon cancer progression. As a confirm to these observations, the erk inhibitor U0126 and the EGFR inhibitors Tyrphostin and Cetuximab were able to contrast AREG induction. Our data provide evidence that Celecoxib directly activates MF empowering EGFR signaling. According to these results the association with EGFR (or erk1-2) inhibitors could abolish the off-target activity of Celecoxib, possibly extending the potential of this drug for colon cancer prevention. CI - Copyright (c) 2012 Elsevier Ireland Ltd. All rights reserved. FAU - Benelli, Roberto AU - Benelli R AD - Immunology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino - Istituto Nazionale per la Ricerca sul Cancro (AOUSM-IST), Genoa, Italy. roberto.benelli@istge.it FAU - Vene, Roberta AU - Vene R FAU - Minghelli, Simona AU - Minghelli S FAU - Carlone, Sebastiano AU - Carlone S FAU - Gatteschi, Beatrice AU - Gatteschi B FAU - Ferrari, Nicoletta AU - Ferrari N LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120923 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Pyrazoles) RN - 0 (Sulfonamides) RN - EC 2.7.10.1 (ErbB Receptors) RN - JCX84Q7J1L (Celecoxib) SB - IM MH - Amphiregulin MH - Celecoxib MH - Cell Line MH - Cell Proliferation/*drug effects MH - Colon/*drug effects/metabolism MH - EGF Family of Proteins MH - ErbB Receptors/metabolism MH - Glycoproteins/*biosynthesis MH - Humans MH - Intercellular Signaling Peptides and Proteins/*biosynthesis MH - MAP Kinase Signaling System MH - Myofibroblasts/*drug effects/metabolism MH - Pyrazoles/*pharmacology MH - Sulfonamides/*pharmacology EDAT- 2012/09/27 06:00 MHDA- 2013/01/11 06:00 CRDT- 2012/09/27 06:00 PHST- 2012/07/20 00:00 [received] PHST- 2012/09/12 00:00 [revised] PHST- 2012/09/12 00:00 [accepted] PHST- 2012/09/27 06:00 [entrez] PHST- 2012/09/27 06:00 [pubmed] PHST- 2013/01/11 06:00 [medline] AID - S0304-3835(12)00545-9 [pii] AID - 10.1016/j.canlet.2012.09.008 [doi] PST - ppublish SO - Cancer Lett. 2013 Jan 1;328(1):73-82. doi: 10.1016/j.canlet.2012.09.008. Epub 2012 Sep 23.