TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT

Autor: Aymeric Morlé, Delphine Merino, Olivier Micheau, Bruno Robert, Elisabetta Iessi, Eric Solary, Sarah Shirley, Carmen Garrido, Najoua Lalaoui, Alexandre Morizot, Guillaume Jacquemin
Přispěvatelé: Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Ligue Nationale contre le Cancer, Ministère de la recherche, ARC (Association pour la Recherche sur le Cancer), INSERM et Conseil Regional de Bourgogne, Micheau, Olivier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Proliferation index
lcsh:Medicine
TNF-Related Apoptosis-Inducing Ligand
HeLa
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Molecular Cell Biology
Basic Cancer Research
Membrane Receptor Signaling
Enzyme Inhibitors
lcsh:Science
Phosphoinositide-3 Kinase Inhibitors
0303 health sciences
Multidisciplinary
Cell Death
biology
apoptosis
3. Good health
Cell biology
Oncology
030220 oncology & carcinogenesis
Medicine
Female
Signal transduction
Research Article
Signal Transduction
Programmed cell death
Morpholines
proliferation
Blotting
Western
Mice
Nude
03 medical and health sciences
TRAIL-R4
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Biology
[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
030304 developmental biology
Cell growth
Akt
Cell Membrane
lcsh:R
PTEN Phosphohydrolase
Neoplasms
Experimental
biology.organism_classification
Tumor Necrosis Factor Decoy Receptors
Chromones
Apoptosis
lcsh:Q
Proto-Oncogene Proteins c-akt
HeLa Cells
Zdroj: PLoS ONE
PLoS ONE, 2011, 6 (5), pp.e19679. ⟨10.1371/journal.pone.0019679⟩
PLoS ONE, Vol 6, Iss 5, p e19679 (2011)
PLoS ONE, Public Library of Science, 2011, 6 (5), pp.e19679. ⟨10.1371/journal.pone.0019679⟩
PLoS ONE, Public Library of Science, 2011, 6 (5), pp.e19679. 〈10.1371/journal.pone.0019679〉
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0019679⟩
Popis: International audience; 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
Databáze: OpenAIRE
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