title: TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT.
abstract: BACKGROUND
  TRAIL/Apo2L is a pro-apoptotic ligand of the TNF family that engages the apoptotic machinery through two pro-apoptotic receptors, TRAIL-R1 and TRAIL-R2. This cell death program is tightly controlled by two antagonistic receptors, TRAIL-R3 and TRAIL-R4, both devoid of a functional death domain, an intracellular region of the receptor, required for the recruitment and the activation of initiator caspases. Upon TRAIL-binding, TRAIL-R4 forms a heteromeric complex with the agonistic receptor TRAIL-R2 leading to reduced caspase-8 activation and apoptosis.
  
  
  RESULTS
  We provide evidence that TRAIL-R4 can also exhibit, in a ligand independent manner, signaling properties in the cervical carcinoma cell line HeLa, through Akt. Ectopic expression of TRAIL-R4 in HeLa cells induced morphological changes, with cell rounding, loss of adherence and markedly enhanced cell proliferation in vitro and tumor growth in vivo. Disruption of the PI3K/Akt pathway using the pharmacological inhibitor LY294002, siRNA targeting the p85 regulatory subunit of phosphatidylinositol-3 kinase, or by PTEN over-expression, partially restored TRAIL-mediated apoptosis in these cells. Moreover, the Akt inhibitor, LY294002, restituted normal cell proliferation index in HeLa cells expressing TRAIL-R4.
  
  
  CONCLUSIONS
  Altogether, these results indicate that, besides its ability to directly inhibit TRAIL-induced cell death at the membrane, TRAIL-R4 can also trigger the activation of signaling pathways leading to cell survival and proliferation in HeLa cells. Our findings raise the possibility that TRAIL-R4 may contribute to cervical carcinogenesis.
authors.affiliation: U866, INSERM (Institut National de la Santé et de la Recherche Médicale), Dijon, France.
authors.forename: Najoua
authors.initials: N
authors.lastname: Lalaoui
authors.forename: Aymeric
authors.initials: A
authors.lastname: Morlé
authors.forename: Delphine
authors.initials: D
authors.lastname: Mérino
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquemin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iessi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morizot
authors.forename: Sarah
authors.initials: S
authors.lastname: Shirley
authors.forename: Bruno
authors.initials: B
authors.lastname: Robert
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053319:Tumor Necrosis Factor Decoy Receptors / Q000378:metabolism*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; C451501:TNFRSF10D protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human