title: Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1.
abstract: 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(2+)-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(2+) 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(2+) 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.
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
authors: Hui-Hua
authors: HH
authors: Chang
authors: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors: Steven H
authors: SH
authors: Young
authors: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors: James
authors: J
authors: Sinnett-Smith
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
authors: Caroline Ei Ne
authors: CE
authors: Chou
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
authors: Aune
authors: A
authors: Moro
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
authors: Kathleen M
authors: KM
authors: Hertzer
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
authors: Oscar Joe
authors: OJ
authors: Hines
authors: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors: Enrique
authors: E
authors: Rozengurt
authors: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California; and GEibl@mednet.ucla.edu.
authors: Guido
authors: G
authors: Eibl
mesh_terms: D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C508840:IL23A protein, human; D053760:Interleukin-23 Subunit p19; D046912:Multiprotein Complexes; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D002118:Calcium
keywords: mammalian target of rapamycin complex 1; obesity; pancreatic cancer; prostaglandin E2