Abstract 5291: Signaling cross-talks in obesity-associated pancreatic cancer: Interaction between prostaglandin E2 signaling and mTOR pathway
Authors: Chang Hui-Hua , Eibl Guido 
Published: May 2015

Abstract
Obesity is a known risk factor for human cancers, including pancreatic cancer, and is associated with inflammation and insulin-resistance. The pro-inflammatory eicosanoid prostaglandin E2 (PGE2), which signals via EP receptors and cAMP, and insulin-like growth factor 1 (IGF-1), which is elevated in insulin resistance and activates the Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling module, have both been shown to play critical roles in pancreatic cancer development and growth. The aim of this study was to investigate an unexplored crosstalk between the PGE2/EP/cAMP and IGF-1/Akt/mTORC1 signaling pathways in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In our studies, human pancreatic cancer cell lines were used, and the activation of signaling molecules was mainly assessed by Western blotting analysis. In multiple cell lines (Capan-2, HPAF-II, Mia PaCa-2, and PANC-1), PGE2 exposure increased intracellular cAMP levels measured by enzyme immunoassay, indicating the activation of Gs alpha-coupled EP receptors (EP2 and/or EP4). In PANC-1 cells, which showed the greatest responsiveness of cAMP induction, PGE2 dose- and time-dependently increased the phosphorylation of S6 ribosomal protein (S6rpSer235/236) that is downstream of mTORC1, suggesting a crosstalk between PGE2/cAMP and mTORC1. In addition, the effect of PGE2 on phospho-S6rp was mimicked by Forskolin, a pharmacological cAMP stimulator. Importantly, PGE2 enhanced the effect of IGF-1 on S6rp phosphorylation, supporting the existence of a positive reinforcement by the interaction between the two pathways. Interestingly, PGE2 and forskolin had no effect on Akt phosphorylation (Thr308 and Ser473), suggesting a link downstream of Akt. The activation of the mTORC-1 pathway upon PGE2 treatment paralleled an increase in the phosphorylation of cAMP response element-binding protein (CREB), a substrate of protein kinase A (PKA). In the presence of the PKA inhibitor H89, baseline phosphorylation of S6rp and PGE2-activated S6rp phosphorylation were reduced, indicating a role of PKA in the crosstalk. In summary, our data provide the first evidence of a crosstalk between the PGE2/EP2/cAMP and IGF-1/Akt/mTORC1 signaling pathways. Since both pathways are over-activated in obesity-associated cancers, this interaction may be of great importance in elucidating the tumor-promoting effects of obesity in pancreatic cancer. Ultimately, a detailed understanding of these molecular links may provide mechanistic targets for novel efficacious interventions devoid of adverse effects for pancreatic cancer in an increasingly obese population.
Citation Format: Hui-Hua Chang, Guido Eibl. Signaling cross-talks in obesity-associated pancreatic cancer: Interaction between prostaglandin E2 signaling and mTOR pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5291. doi:10.1158/1538-7445.AM2014-5291