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

• Published in: PloS one 2011-05, Vol.6 (5), p.e19679
• Main Authors: Lalaoui, Najoua, Morlé, Aymeric, Mérino, Delphine, Jacquemin, Guillaume, Iessi, Elisabetta, Morizot, Alexandre, Shirley, Sarah, Robert, Bruno, Solary, Eric, Garrido, Carmen, Micheau, Olivier
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; AKT protein; Animals; Apoptosis; Biochemistry, Molecular Biology; Biology; Blotting, Western; Carcinogenesis; Carcinogens; Carcinoma; Caspase; Caspase-8; Cell death; Cell growth; Cell Membrane - metabolism; Cell Proliferation; Cell survival; Cervical cancer; Cervical carcinoma; Cervix; Chromones - pharmacology; Disruption; Ectopic expression; Enzyme Inhibitors - pharmacology; Female; Growth; HeLa Cells; Humans; Inhibitors; Kinases; Life Sciences; Machinery and equipment; Medicine; Mice; Mice, Nude; Morpholines - pharmacology; Mortality; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Overexpression; Pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; PTEN protein; Receptors; Rounding; Signal Transduction; Signaling; siRNA; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL protein; Tumor necrosis factor; Tumor Necrosis Factor Decoy Receptors - metabolism; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019679

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. 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. 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.