CALL FOR PAPERS Physical Biology of Cancer Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/ PKA- and EP1/Ca -mediated mechanism in the human pancreatic carcinoma cell line PANC-1

Chang H, Young SH, Sinnett-Smith J, Chou CE, Moro A, Hertzer KM, Hines OJ, Rozengurt E, Eibl G. Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKAand EP1/Ca -mediated mechanism in the human pancreatic carcinoma cell line PANC-1. Am J Physiol Cell Physiol 309: C639–C649, 2015. First published August 26, 2015; doi:10.1152/ajpcell.00417.2014.— Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/ cAMP/PKA and EP1/Ca signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.