Abstract 1130: mPGES-1 drives the oncogenic potential of EGFR signaling

Abstract Prostaglandins, mostly PGE-2, have assumed an important role in cancer biology. Regarding of PGE-2 production, recent investigations have focused on PGE-2 synthases (mPGEs-1, mPGEs-2 and cPGEs), specifically on mPGEs-1, the only inducible enzyme among those so far identified in cells. Whereas cPGEs and mPGEs-2 are constitutively expressed at relatively low levels, mPGEs-1 is highly inducible by pro-inflammatory stimuli. mPGEs-1 upregulation has been detected in many epithelial tumors, and its silencing has been reported to reduce preneoplastic lesions. Despite the evidence linking mPGEs-1 and tumorigenesis, most studies investigating the inducible nature of the enzyme in cultured cells have been performed using a variety of inflammatory stimuli, while little is known about the behavior of the enzyme in tumor cells challenged with oncogenic stimuli. In this work we investigated mPGES-1 regulation in cultured epithelial tumor cells exposed to epidermal growth factor (EGF), an oncogene product which, through its receptor, EGF-receptor, is responsible for tumorigenisis in a wide array of solid tumors. We used three cell lines, representative of colon (HT-29), epidermoid (A431) and lung (A549) tumors, examining the expression of mPGEs-1 protein following EGF-receptor activation by EGF. We found that cells responded to EGF-receptor stimulation with a transient surge of the transcription factor Egr-1, its translocation from cytosol to necleus, an increase of mPGEs-1 mRNA and protein, as well as, an enhanced PGE-2 formation. These changes were suppressed by silencing Egr-1 and by EGF-receptor blockade or by inhibitors of the EGF-receptor-dependent mediators, such as MAP-kinase, ERK1/2. Moreover, cell activation through EGF-receptor induced a tumorigenic phenotype, detectable by clonogenic assay, which regressed when mPGEs-1 was silenced. We also explored the effect of inhibiting the EGF-receptor in A431 xenografts on mPGEs-1 expression and tumor growth, finding a parallel decline of both. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1130. doi:10.1158/1538-7445.AM2011-1130