title: PGE2-induced colon cancer growth is mediated by mTORC1.
abstract: The inflammatory prostaglandin E2 (PGE2) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE2 directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE2-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE2 increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE2 EP4 receptor was responsible for transducing the signal to mTORC1. Moreover, PGE2 increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE2-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE2 increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE2 mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland. Electronic address: Marc.dufour@chuv.ch.
authors.forename: Marc
authors.initials: M
authors.lastname: Dufour
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland. Electronic address: Seraina.faes@chuv.ch.
authors.forename: Seraina
authors.initials: S
authors.lastname: Faes
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland. Electronic address: Anne.meuwly-Dormond@chuv.ch.
authors.forename: Anne
authors.initials: A
authors.lastname: Dormond-Meuwly
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland. Electronic address: Demartines@chuv.ch.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.affiliation: Department of Visceral Surgery, University Hospital of Lausanne, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland. Electronic address: Olivier.dormond@chuv.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000209:etiology*; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D046912:Multiprotein Complexes; D058309:Receptors, Prostaglandin E, EP4 Subtype; D042461:Vascular Endothelial Growth Factor A; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D015232:Dinoprostone
keywords: Colon cancer; PGE(2); Rapamycin; Signaling; mTORC1