Hypoxia-induced autophagy contributes to radioresistance via c-Jun-mediated Beclin1 expression in lung cancer cells.
Identifieur interne : 001025 ( Main/Exploration ); précédent : 001024; suivant : 001026Hypoxia-induced autophagy contributes to radioresistance via c-Jun-mediated Beclin1 expression in lung cancer cells.
Auteurs : Yan-Mei Zou [République populaire de Chine] ; Guang-Yuan Hu [République populaire de Chine] ; Xue-Qi Zhao [République populaire de Chine] ; Tao Lu [République populaire de Chine] ; Feng Zhu [République populaire de Chine] ; Shi-Ying Yu [République populaire de Chine] ; Hua Xiong [République populaire de Chine]Source :
- Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban [ 1672-0733 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Autophagie, Bécline-1, Charge tumorale (génétique), Humains, Hypoxie cellulaire, Immunotransfert, Lignée cellulaire tumorale, Microscopie de fluorescence, Phosphorylation, Protéines associées aux microtubules (génétique), Protéines associées aux microtubules (métabolisme), Protéines membranaires (génétique), Protéines membranaires (métabolisme), Protéines proto-oncogènes c-jun (métabolisme), Protéines régulatrices de l'apoptose (génétique), Protéines régulatrices de l'apoptose (métabolisme), Protéines à fluorescence verte (génétique), Protéines à fluorescence verte (métabolisme), RT-PCR, Radiotolérance (génétique), Régulation de l'expression des gènes tumoraux (effets des radiations), Souris nude, Sous-unité alpha du facteur-1 induit par l'hypoxie (métabolisme), Survie cellulaire (effets des radiations), Survie cellulaire (génétique), Transplantation hétérologue, Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (génétique), Tumeurs du poumon (métabolisme).
- MESH :
- anatomopathologie : Tumeurs du poumon.
- effets des radiations : Régulation de l'expression des gènes tumoraux, Survie cellulaire.
- génétique : Charge tumorale, Protéines associées aux microtubules, Protéines membranaires, Protéines régulatrices de l'apoptose, Protéines à fluorescence verte, Radiotolérance, Survie cellulaire, Tumeurs du poumon.
- métabolisme : Protéines associées aux microtubules, Protéines membranaires, Protéines proto-oncogènes c-jun, Protéines régulatrices de l'apoptose, Protéines à fluorescence verte, Sous-unité alpha du facteur-1 induit par l'hypoxie, Tumeurs du poumon.
- Animaux, Autophagie, Bécline-1, Humains, Hypoxie cellulaire, Immunotransfert, Lignée cellulaire tumorale, Microscopie de fluorescence, Phosphorylation, RT-PCR, Souris nude, Transplantation hétérologue.
English descriptors
- KwdEn :
- Animals, Apoptosis Regulatory Proteins (genetics), Apoptosis Regulatory Proteins (metabolism), Autophagy, Beclin-1, Cell Hypoxia, Cell Line, Tumor, Cell Survival (genetics), Cell Survival (radiation effects), Gene Expression Regulation, Neoplastic (radiation effects), Green Fluorescent Proteins (genetics), Green Fluorescent Proteins (metabolism), Humans, Hypoxia-Inducible Factor 1, alpha Subunit (metabolism), Immunoblotting, Lung Neoplasms (genetics), Lung Neoplasms (metabolism), Lung Neoplasms (pathology), Membrane Proteins (genetics), Membrane Proteins (metabolism), Mice, Nude, Microscopy, Fluorescence, Microtubule-Associated Proteins (genetics), Microtubule-Associated Proteins (metabolism), Phosphorylation, Proto-Oncogene Proteins c-jun (metabolism), Radiation Tolerance (genetics), Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Tumor Burden (genetics).
- MESH :
- chemical , genetics : Apoptosis Regulatory Proteins, Green Fluorescent Proteins, Membrane Proteins, Microtubule-Associated Proteins.
- chemical , metabolism : Apoptosis Regulatory Proteins, Green Fluorescent Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Membrane Proteins, Microtubule-Associated Proteins, Proto-Oncogene Proteins c-jun.
- genetics : Cell Survival, Lung Neoplasms, Radiation Tolerance, Tumor Burden.
- metabolism : Lung Neoplasms.
- pathology : Lung Neoplasms.
- radiation effects : Cell Survival, Gene Expression Regulation, Neoplastic.
- Animals, Autophagy, Beclin-1, Cell Hypoxia, Cell Line, Tumor, Humans, Immunoblotting, Mice, Nude, Microscopy, Fluorescence, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous.
Abstract
Reduced radiosensitivity of lung cancer cells represents a pivotal obstacle in clinical oncology. The hypoxia-inducible factor (HIF)-1α plays a crucial role in radiosensitivity, but the detailed mechanisms remain elusive. A relationship has been suggested to exist between hypoxia and autophagy recently. In the current study, we studied the effect of hypoxia-induced autophagy on radioresistance in lung cancer cell lines. A549 and H1299 cells were cultured under normoxia or hypoxia, followed by irradiation at dosage ranging from 0 to 8 Gy. Clonogenic assay was performed to calculate surviving fraction. EGFP-LC3 plasmid was stably transfected into cells to monitor autophagic processes. Western blotting was used to evaluate the protein expression levels of HIF-1α, c-Jun, phosphorylated c-Jun, Beclin 1, LC3 and p62. The mRNA levels of Beclin 1 were detected by qRT-PCR. We found that under hypoxia, both A549 and H1299 cells were radio-resistant compared with normoxia. Hypoxia-induced elevated HIF-1α protein expression preferentially triggered autophagy, accompanied by LC3 induction, EGFP-LC3 puncta and p62 degradation. In the meantime, HIF-1α increased downstream c-Jun phosphorylation, which in turn upregulated Beclin 1 mRNA and protein expression. The upregulation of Beclin 1 expression, instead of HIF-1α, could be blocked by SP600125 (a specific inhibitor of c-Jun NH2-terminal kinase), followed by suppression of autophagy. Under hypoxia, combined treatment of irradiation and chloroquine (a potent autophagy inhibitor) significantly decreased the survival potential of lung cancer cells in vitro and in vivo. In conclusion, hypoxia-induced autophagy through evaluating Beclin1 expression may be considered as a target to reverse the radioresistance in cancer cells.
DOI: 10.1007/s11596-014-1349-2
PubMed: 25318890
Affiliations:
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430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Tao" sort="Lu, Tao" uniqKey="Lu T" first="Tao" last="Lu">Tao Lu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Zhu, Feng" sort="Zhu, Feng" uniqKey="Zhu F" first="Feng" last="Zhu">Feng Zhu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Yu, Shi Ying" sort="Yu, Shi Ying" uniqKey="Yu S" first="Shi-Ying" last="Yu">Shi-Ying Yu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Xiong, Hua" sort="Xiong, Hua" uniqKey="Xiong H" 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Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Hu, Guang Yuan" sort="Hu, Guang Yuan" uniqKey="Hu G" first="Guang-Yuan" last="Hu">Guang-Yuan Hu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Zhao, Xue Qi" sort="Zhao, Xue Qi" uniqKey="Zhao X" first="Xue-Qi" last="Zhao">Xue-Qi Zhao</name><affiliation wicri:level="1"><nlm:affiliation>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Tao" sort="Lu, Tao" uniqKey="Lu T" first="Tao" last="Lu">Tao Lu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Zhu, Feng" sort="Zhu, Feng" uniqKey="Zhu F" first="Feng" last="Zhu">Feng Zhu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Yu, Shi Ying" sort="Yu, Shi Ying" uniqKey="Yu S" first="Shi-Ying" last="Yu">Shi-Ying Yu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author><author><name sortKey="Xiong, Hua" sort="Xiong, Hua" uniqKey="Xiong H" first="Hua" last="Xiong">Hua Xiong</name><affiliation wicri:level="1"><nlm:affiliation>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. cnhxiong@163.com.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030</wicri:regionArea><wicri:noRegion>430030</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban</title><idno type="ISSN">1672-0733</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Apoptosis Regulatory Proteins (genetics)</term><term>Apoptosis Regulatory Proteins (metabolism)</term><term>Autophagy</term><term>Beclin-1</term><term>Cell Hypoxia</term><term>Cell Line, Tumor</term><term>Cell Survival (genetics)</term><term>Cell Survival (radiation effects)</term><term>Gene Expression Regulation, Neoplastic (radiation effects)</term><term>Green Fluorescent Proteins (genetics)</term><term>Green Fluorescent Proteins (metabolism)</term><term>Humans</term><term>Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)</term><term>Immunoblotting</term><term>Lung Neoplasms (genetics)</term><term>Lung Neoplasms (metabolism)</term><term>Lung Neoplasms (pathology)</term><term>Membrane Proteins (genetics)</term><term>Membrane Proteins (metabolism)</term><term>Mice, Nude</term><term>Microscopy, Fluorescence</term><term>Microtubule-Associated Proteins (genetics)</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Phosphorylation</term><term>Proto-Oncogene Proteins c-jun (metabolism)</term><term>Radiation Tolerance (genetics)</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Transplantation, Heterologous</term><term>Tumor Burden (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Autophagie</term><term>Bécline-1</term><term>Charge tumorale (génétique)</term><term>Humains</term><term>Hypoxie cellulaire</term><term>Immunotransfert</term><term>Lignée cellulaire tumorale</term><term>Microscopie de fluorescence</term><term>Phosphorylation</term><term>Protéines associées aux microtubules (génétique)</term><term>Protéines associées aux microtubules (métabolisme)</term><term>Protéines membranaires (génétique)</term><term>Protéines membranaires (métabolisme)</term><term>Protéines proto-oncogènes c-jun (métabolisme)</term><term>Protéines régulatrices de l'apoptose (génétique)</term><term>Protéines régulatrices de l'apoptose (métabolisme)</term><term>Protéines à fluorescence verte (génétique)</term><term>Protéines à fluorescence verte (métabolisme)</term><term>RT-PCR</term><term>Radiotolérance (génétique)</term><term>Régulation de l'expression des gènes tumoraux (effets des radiations)</term><term>Souris nude</term><term>Sous-unité alpha du facteur-1 induit par l'hypoxie (métabolisme)</term><term>Survie cellulaire (effets des radiations)</term><term>Survie cellulaire (génétique)</term><term>Transplantation hétérologue</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Tumeurs du poumon (génétique)</term><term>Tumeurs du poumon (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Apoptosis Regulatory Proteins</term><term>Green Fluorescent Proteins</term><term>Membrane Proteins</term><term>Microtubule-Associated Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Apoptosis Regulatory Proteins</term><term>Green Fluorescent Proteins</term><term>Hypoxia-Inducible Factor 1, alpha Subunit</term><term>Membrane Proteins</term><term>Microtubule-Associated Proteins</term><term>Proto-Oncogene Proteins c-jun</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="effets des radiations" xml:lang="fr"><term>Régulation de l'expression des gènes tumoraux</term><term>Survie cellulaire</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Survival</term><term>Lung Neoplasms</term><term>Radiation Tolerance</term><term>Tumor Burden</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Charge tumorale</term><term>Protéines associées aux microtubules</term><term>Protéines membranaires</term><term>Protéines régulatrices de l'apoptose</term><term>Protéines à fluorescence verte</term><term>Radiotolérance</term><term>Survie cellulaire</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines associées aux microtubules</term><term>Protéines membranaires</term><term>Protéines proto-oncogènes c-jun</term><term>Protéines régulatrices de l'apoptose</term><term>Protéines à fluorescence verte</term><term>Sous-unité alpha du facteur-1 induit par l'hypoxie</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="radiation effects" xml:lang="en"><term>Cell Survival</term><term>Gene Expression Regulation, Neoplastic</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Autophagy</term><term>Beclin-1</term><term>Cell Hypoxia</term><term>Cell Line, Tumor</term><term>Humans</term><term>Immunoblotting</term><term>Mice, Nude</term><term>Microscopy, Fluorescence</term><term>Phosphorylation</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Transplantation, Heterologous</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Autophagie</term><term>Bécline-1</term><term>Humains</term><term>Hypoxie cellulaire</term><term>Immunotransfert</term><term>Lignée cellulaire tumorale</term><term>Microscopie de fluorescence</term><term>Phosphorylation</term><term>RT-PCR</term><term>Souris nude</term><term>Transplantation hétérologue</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Reduced radiosensitivity of lung cancer cells represents a pivotal obstacle in clinical oncology. The hypoxia-inducible factor (HIF)-1α plays a crucial role in radiosensitivity, but the detailed mechanisms remain elusive. A relationship has been suggested to exist between hypoxia and autophagy recently. In the current study, we studied the effect of hypoxia-induced autophagy on radioresistance in lung cancer cell lines. A549 and H1299 cells were cultured under normoxia or hypoxia, followed by irradiation at dosage ranging from 0 to 8 Gy. Clonogenic assay was performed to calculate surviving fraction. EGFP-LC3 plasmid was stably transfected into cells to monitor autophagic processes. Western blotting was used to evaluate the protein expression levels of HIF-1α, c-Jun, phosphorylated c-Jun, Beclin 1, LC3 and p62. The mRNA levels of Beclin 1 were detected by qRT-PCR. We found that under hypoxia, both A549 and H1299 cells were radio-resistant compared with normoxia. Hypoxia-induced elevated HIF-1α protein expression preferentially triggered autophagy, accompanied by LC3 induction, EGFP-LC3 puncta and p62 degradation. In the meantime, HIF-1α increased downstream c-Jun phosphorylation, which in turn upregulated Beclin 1 mRNA and protein expression. The upregulation of Beclin 1 expression, instead of HIF-1α, could be blocked by SP600125 (a specific inhibitor of c-Jun NH2-terminal kinase), followed by suppression of autophagy. Under hypoxia, combined treatment of irradiation and chloroquine (a potent autophagy inhibitor) significantly decreased the survival potential of lung cancer cells in vitro and in vivo. In conclusion, hypoxia-induced autophagy through evaluating Beclin1 expression may be considered as a target to reverse the radioresistance in cancer cells. </div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zou, Yan Mei" sort="Zou, Yan Mei" uniqKey="Zou Y" first="Yan-Mei" last="Zou">Yan-Mei Zou</name></noRegion><name sortKey="Hu, Guang Yuan" sort="Hu, Guang Yuan" uniqKey="Hu G" first="Guang-Yuan" last="Hu">Guang-Yuan Hu</name><name sortKey="Lu, Tao" sort="Lu, Tao" uniqKey="Lu T" first="Tao" last="Lu">Tao Lu</name><name sortKey="Xiong, Hua" sort="Xiong, Hua" uniqKey="Xiong H" first="Hua" last="Xiong">Hua Xiong</name><name sortKey="Yu, Shi Ying" sort="Yu, Shi Ying" uniqKey="Yu S" first="Shi-Ying" last="Yu">Shi-Ying Yu</name><name sortKey="Zhao, Xue Qi" sort="Zhao, Xue Qi" uniqKey="Zhao X" first="Xue-Qi" last="Zhao">Xue-Qi Zhao</name><name sortKey="Zhu, Feng" sort="Zhu, Feng" uniqKey="Zhu F" first="Feng" last="Zhu">Feng Zhu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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