The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis.

Détails

ID Serval
serval:BIB_9F4B7C9D451B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis.
Périodique
Journal of immunology
Auteur(s)
Noman M.Z., Buart S., Van Pelt J., Richon C., Hasmim M., Leleu N., Suchorska W.M., Jalil A., Lecluse Y., El Hage F., Giuliani M., Pichon C., Azzarone B., Mazure N., Romero P., Mami-Chouaib F., Chouaib S.
ISSN
1550-6606[electronic]
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
182
Numéro
6
Pages
3510-3521
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.
Mots-clé
Anoxia/immunology, Anoxia/metabolism, Cell Line, Tumor, Clone Cells, Cytotoxicity, Immunologic, Gene Expression Regulation, Neoplastic/immunology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis, Hypoxia-Inducible Factor 1, alpha Subunit/physiology, Immunity, Innate, Lung Neoplasms/immunology, Lung Neoplasms/metabolism, STAT3 Transcription Factor/antagonists & inhibitors, STAT3 Transcription Factor/biosynthesis, T-Lymphocytes, Cytotoxic/immunology, T-Lymphocytes, Cytotoxic/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/01/2010 14:55
Dernière modification de la notice
20/08/2019 15:05
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