Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.
Identifieur interne : 001476 ( Main/Curation ); précédent : 001475; suivant : 001477Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.
Auteurs : Muhammad Zaeem Noman [France] ; Bassam Janji ; Bozena Kaminska ; Kris Van Moer ; Sandrine Pierson ; Piotr Przanowski ; Stéphanie Buart ; Guy Berchem ; Pedro Romero ; Fathia Mami-Chouaib ; Salem ChouaibSource :
- Cancer research [ 1538-7445 ] ; 2011.
Descripteurs français
- KwdFr :
- Animaux, Autophagie (immunologie), Facteur de transcription STAT-3 (métabolisme), Humains, Hypoxie cellulaire (immunologie), Lignée cellulaire tumorale, Lymphocytes T cytotoxiques (immunologie), Mélanome expérimental (anatomopathologie), Mélanome expérimental (immunologie), Mélanome expérimental (métabolisme), Phosphorylation, Proteasome endopeptidase complex (métabolisme), Protéines adaptatrices de la transduction du signal (métabolisme), Protéines du choc thermique (métabolisme), Souris, Souris de lignée C57BL, Séquestosome-1, Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (immunologie), Tumeurs du poumon (métabolisme), Ubiquitine (métabolisme), src-Family kinases (métabolisme).
- MESH :
- anatomopathologie : Mélanome expérimental, Tumeurs du poumon.
- immunologie : Autophagie, Hypoxie cellulaire, Lymphocytes T cytotoxiques, Mélanome expérimental, Tumeurs du poumon.
- métabolisme : Facteur de transcription STAT-3, Mélanome expérimental, Proteasome endopeptidase complex, Protéines adaptatrices de la transduction du signal, Protéines du choc thermique, Tumeurs du poumon, Ubiquitine, src-Family kinases.
- Animaux, Humains, Lignée cellulaire tumorale, Phosphorylation, Souris, Souris de lignée C57BL, Séquestosome-1.
English descriptors
- KwdEn :
- Adaptor Proteins, Signal Transducing (metabolism), Animals, Autophagy (immunology), Cell Hypoxia (immunology), Cell Line, Tumor, Heat-Shock Proteins (metabolism), Humans, Lung Neoplasms (immunology), Lung Neoplasms (metabolism), Lung Neoplasms (pathology), Melanoma, Experimental (immunology), Melanoma, Experimental (metabolism), Melanoma, Experimental (pathology), Mice, Mice, Inbred C57BL, Phosphorylation, Proteasome Endopeptidase Complex (metabolism), STAT3 Transcription Factor (metabolism), Sequestosome-1 Protein, T-Lymphocytes, Cytotoxic (immunology), Ubiquitin (metabolism), src-Family Kinases (metabolism).
- MESH :
- chemical , metabolism : Adaptor Proteins, Signal Transducing, Heat-Shock Proteins, Proteasome Endopeptidase Complex, STAT3 Transcription Factor, Ubiquitin, src-Family Kinases.
- immunology : Autophagy, Cell Hypoxia, Lung Neoplasms, Melanoma, Experimental, T-Lymphocytes, Cytotoxic.
- metabolism : Lung Neoplasms, Melanoma, Experimental.
- pathology : Lung Neoplasms, Melanoma, Experimental.
- Animals, Cell Line, Tumor, Humans, Mice, Mice, Inbred C57BL, Phosphorylation, Sequestosome-1 Protein.
Abstract
The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.
DOI: 10.1158/0008-5472.CAN-11-1094
PubMed: 21810913
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pubmed:21810913Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adaptor Proteins, Signal Transducing (metabolism)</term>
<term>Animals</term>
<term>Autophagy (immunology)</term>
<term>Cell Hypoxia (immunology)</term>
<term>Cell Line, Tumor</term>
<term>Heat-Shock Proteins (metabolism)</term>
<term>Humans</term>
<term>Lung Neoplasms (immunology)</term>
<term>Lung Neoplasms (metabolism)</term>
<term>Lung Neoplasms (pathology)</term>
<term>Melanoma, Experimental (immunology)</term>
<term>Melanoma, Experimental (metabolism)</term>
<term>Melanoma, Experimental (pathology)</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Phosphorylation</term>
<term>Proteasome Endopeptidase Complex (metabolism)</term>
<term>STAT3 Transcription Factor (metabolism)</term>
<term>Sequestosome-1 Protein</term>
<term>T-Lymphocytes, Cytotoxic (immunology)</term>
<term>Ubiquitin (metabolism)</term>
<term>src-Family Kinases (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Autophagie (immunologie)</term>
<term>Facteur de transcription STAT-3 (métabolisme)</term>
<term>Humains</term>
<term>Hypoxie cellulaire (immunologie)</term>
<term>Lignée cellulaire tumorale</term>
<term>Lymphocytes T cytotoxiques (immunologie)</term>
<term>Mélanome expérimental (anatomopathologie)</term>
<term>Mélanome expérimental (immunologie)</term>
<term>Mélanome expérimental (métabolisme)</term>
<term>Phosphorylation</term>
<term>Proteasome endopeptidase complex (métabolisme)</term>
<term>Protéines adaptatrices de la transduction du signal (métabolisme)</term>
<term>Protéines du choc thermique (métabolisme)</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Séquestosome-1</term>
<term>Tumeurs du poumon (anatomopathologie)</term>
<term>Tumeurs du poumon (immunologie)</term>
<term>Tumeurs du poumon (métabolisme)</term>
<term>Ubiquitine (métabolisme)</term>
<term>src-Family kinases (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term>
<term>Heat-Shock Proteins</term>
<term>Proteasome Endopeptidase Complex</term>
<term>STAT3 Transcription Factor</term>
<term>Ubiquitin</term>
<term>src-Family Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Mélanome expérimental</term>
<term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Autophagie</term>
<term>Hypoxie cellulaire</term>
<term>Lymphocytes T cytotoxiques</term>
<term>Mélanome expérimental</term>
<term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Autophagy</term>
<term>Cell Hypoxia</term>
<term>Lung Neoplasms</term>
<term>Melanoma, Experimental</term>
<term>T-Lymphocytes, Cytotoxic</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung Neoplasms</term>
<term>Melanoma, Experimental</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur de transcription STAT-3</term>
<term>Mélanome expérimental</term>
<term>Proteasome endopeptidase complex</term>
<term>Protéines adaptatrices de la transduction du signal</term>
<term>Protéines du choc thermique</term>
<term>Tumeurs du poumon</term>
<term>Ubiquitine</term>
<term>src-Family kinases</term>
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<term>Melanoma, Experimental</term>
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<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Phosphorylation</term>
<term>Sequestosome-1 Protein</term>
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<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Phosphorylation</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.</div>
</front>
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