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Prostaglandins induce early growth response 1 transcription factor mediated microsomal prostaglandin E2 synthase up-regulation for colorectal cancer progression

2015; Impact Journals LLC; Volume: 6; Issue: 37 Linguagem: Inglês

10.18632/oncotarget.5402

1949-2553

Kostas Stamatakis, Marta Jiménez-Martínez, Alba Jiménez-Segovia, Isabel Chico‐Calero, Elisa Conde, Javier Galán‐Martínez, Julia E. Ruíz, Alejandro Pascual, Beatriz Barrocal, Ricardo López‐Pérez, Laura García‐Bermejo, Manuel Fresno,

NF-κB Signaling Pathways

// Konstantinos Stamatakis 1, 3 , Marta Jimenez-Martinez 1 , Alba Jimenez-Segovia 1 , Isabel Chico-Calero 1 , Elisa Conde 2 , Javier Galán-Martínez 1 , Julia Ruiz 1 , Alejandro Pascual 2 , Beatriz Barrocal 1 , Ricardo López-Pérez 1 , María Laura García-Bermejo 2 , Manuel Fresno 1, 3 1 Centro de Biología Molecular ''Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma de Madrid, Madrid, Spain 2 Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar, Madrid, Spain 3 Instituto Sanitario Princesa de Investigacion Sanitaria (IIS-P), Madrid, Spain Correspondence to: Konstantinos Stamatakis, e-mail: kstamatakis@cbm.csic.es Manuel Fresno, e-mail: mfresno@cbm.csic.es Keywords: cyclooxygenase 2, microsomal prostaglandin E 2 synthase, colorectal adenocarcinoma, early growth response 1 Received: May 07, 2015 Accepted: October 05, 2015 Published: October 17, 2015 ABSTRACT Cyclooxygenase2 (COX2) has been associated with cell growth, invasiveness, tumor progression and metastasis of colorectal carcinomas. However, the downstream prostaglandin (PG)-PG receptor pathway involved in these effects is poorly characterized. We studied the PG-pathway in gene expression databases and we found that PTGS2 (prostaglandin G/H synthase and cyclooxygenase) and PTGES (prostaglandin E synthase) are co-expressed in human colorectal tumors. Moreover, we detected that COX2 and microsomal Prostaglandin E 2 synthase 1 (mPGES1) proteins are both up-regulated in colorectal human tumor biopsies. Using colon carcinoma cell cultures we found that COX2 overexpression significantly increased mPGES1 mRNA and protein. This up-regulation was due to an increase in early growth response 1 (EGR1) levels and its transcriptional activity. EGR1 was induced by COX2-generated PGF 2α . A PGF 2α receptor antagonist, or EGR1 silencing, inhibited the mPGES1 induction by COX2 overexpression. Moreover, using immunodeficient mice, we also demonstrated that both COX2- and mPGES1-overexpressing carcinoma cells were more efficient forming tumors. Our results describe for the first time the molecular pathway correlating PTGS2 and PTGES in colon cancer progression. We demonstrated that in this pathway mPGES1 is induced by COX2 overexpression, via autocrine PGs release, likely PGF 2α , through an EGR1 -dependent mechanism. This signaling provides a molecular explanation to PTGS2 and PTGES association and contribute to colon cancer advance, pointing out novel potential therapeutic targets in this oncological context.