Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Lalaoui N 

PROVIDER: S-EPMC3098831 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Lalaoui Najoua N   Morlé Aymeric A   Mérino Delphine D   Jacquemin Guillaume G   Iessi Elisabetta E   Morizot Alexandre A   Shirley Sarah S   Robert Bruno B   Solary Eric E   Garrido Carmen C   Micheau Olivier O  

PloS one 20110520 5


<h4>Background</h4>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 agonisti  ...[more]

Similar Datasets

| S-EPMC3117243 | biostudies-literature
| S-EPMC10402122 | biostudies-literature
| S-EPMC10945736 | biostudies-literature
| S-EPMC5546445 | biostudies-other
| S-EPMC2394221 | biostudies-other
| S-EPMC2443661 | biostudies-literature
| S-EPMC6354781 | biostudies-literature
| S-EPMC7816514 | biostudies-literature
| S-EPMC6141589 | biostudies-literature
| S-EPMC3268937 | biostudies-literature