A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor.
Identifieur interne : 000D31 ( Main/Exploration ); précédent : 000D30; suivant : 000D32A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor.
Auteurs : Weitao Shen [République populaire de Chine] ; Xuyao Zhang [République populaire de Chine] ; Xiang Fu [République populaire de Chine] ; Jiajun Fan [République populaire de Chine] ; Jingyun Luan [République populaire de Chine] ; Zhonglian Cao [République populaire de Chine] ; Ping Yang [République populaire de Chine] ; Zhongyuan Xu [République populaire de Chine] ; Dianwen Ju [République populaire de Chine]Source :
- Cell death & disease [ 2041-4889 ] ; 2017.
Descripteurs français
- KwdFr :
- 4H-1-Benzopyran-4-ones (pharmacologie), Apoptose (), Arginase (pharmacologie), Autophagie (), Carcinome pulmonaire non à petites cellules (anatomopathologie), Carcinome pulmonaire non à petites cellules (métabolisme), Carcinome pulmonaire non à petites cellules (traitement médicamenteux), Chloroquine (pharmacologie), Humains, Lignée cellulaire tumorale, Morpholines (pharmacologie), Protéines associées aux microtubules (génétique), Protéines associées aux microtubules (métabolisme), Protéines recombinantes (pharmacologie), Protéines tumorales (métabolisme), Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (métabolisme), Tumeurs du poumon (traitement médicamenteux).
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- génétique : Protéines associées aux microtubules.
- métabolisme : Carcinome pulmonaire non à petites cellules, Protéines associées aux microtubules, Protéines tumorales, Tumeurs du poumon.
- pharmacologie : 4H-1-Benzopyran-4-ones, Arginase, Chloroquine, Morpholines, Protéines recombinantes.
- traitement médicamenteux : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- Apoptose, Autophagie, Humains, Lignée cellulaire tumorale.
English descriptors
- KwdEn :
- Apoptosis (drug effects), Arginase (pharmacology), Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (metabolism), Carcinoma, Non-Small-Cell Lung (pathology), Cell Line, Tumor, Chloroquine (pharmacology), Chromones (pharmacology), Humans, Lung Neoplasms (drug therapy), Lung Neoplasms (metabolism), Lung Neoplasms (pathology), Microtubule-Associated Proteins (genetics), Microtubule-Associated Proteins (metabolism), Morpholines (pharmacology), Neoplasm Proteins (metabolism), Recombinant Proteins (pharmacology).
- MESH :
- chemical , genetics : Microtubule-Associated Proteins.
- chemical , metabolism : Microtubule-Associated Proteins, Neoplasm Proteins.
- chemical , pharmacology : Arginase, Chloroquine, Chromones, Morpholines, Recombinant Proteins.
- drug effects : Apoptosis, Autophagy.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- metabolism : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- Cell Line, Tumor, Humans.
Abstract
Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.
DOI: 10.1038/cddis.2017.137
PubMed: 28358368
Affiliations:
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Le document en format XML
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type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zhang, Xuyao" sort="Zhang, Xuyao" uniqKey="Zhang X" first="Xuyao" last="Zhang">Xuyao Zhang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Fu, Xiang" sort="Fu, Xiang" uniqKey="Fu X" first="Xiang" last="Fu">Xiang Fu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Fan, Jiajun" sort="Fan, Jiajun" uniqKey="Fan J" first="Jiajun" last="Fan">Jiajun Fan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Luan, Jingyun" sort="Luan, Jingyun" uniqKey="Luan J" first="Jingyun" last="Luan">Jingyun Luan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Cao, Zhonglian" sort="Cao, Zhonglian" uniqKey="Cao Z" first="Zhonglian" last="Cao">Zhonglian Cao</name><affiliation wicri:level="1"><nlm:affiliation>Department of Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Ping" sort="Yang, Ping" uniqKey="Yang P" first="Ping" last="Yang">Ping Yang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author><author><name sortKey="Xu, Zhongyuan" sort="Xu, Zhongyuan" uniqKey="Xu Z" first="Zhongyuan" last="Xu">Zhongyuan Xu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Ju, Dianwen" sort="Ju, Dianwen" uniqKey="Ju D" first="Dianwen" last="Ju">Dianwen Ju</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203</wicri:regionArea><wicri:noRegion>Shanghai 201203</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cell death & disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis (drug effects)</term><term>Arginase (pharmacology)</term><term>Autophagy (drug effects)</term><term>Carcinoma, Non-Small-Cell Lung (drug therapy)</term><term>Carcinoma, Non-Small-Cell Lung (metabolism)</term><term>Carcinoma, Non-Small-Cell Lung (pathology)</term><term>Cell Line, Tumor</term><term>Chloroquine (pharmacology)</term><term>Chromones (pharmacology)</term><term>Humans</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (metabolism)</term><term>Lung Neoplasms (pathology)</term><term>Microtubule-Associated Proteins (genetics)</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Morpholines (pharmacology)</term><term>Neoplasm Proteins (metabolism)</term><term>Recombinant Proteins (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>4H-1-Benzopyran-4-ones (pharmacologie)</term><term>Apoptose ()</term><term>Arginase (pharmacologie)</term><term>Autophagie ()</term><term>Carcinome pulmonaire non à petites cellules (anatomopathologie)</term><term>Carcinome pulmonaire non à petites cellules (métabolisme)</term><term>Carcinome pulmonaire non à petites cellules (traitement médicamenteux)</term><term>Chloroquine (pharmacologie)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Morpholines (pharmacologie)</term><term>Protéines associées aux microtubules (génétique)</term><term>Protéines associées aux microtubules (métabolisme)</term><term>Protéines recombinantes (pharmacologie)</term><term>Protéines tumorales (métabolisme)</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Tumeurs du poumon (métabolisme)</term><term>Tumeurs du poumon (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Microtubule-Associated Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Microtubule-Associated Proteins</term><term>Neoplasm Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Arginase</term><term>Chloroquine</term><term>Chromones</term><term>Morpholines</term><term>Recombinant Proteins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Autophagy</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines associées aux microtubules</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Protéines associées aux microtubules</term><term>Protéines tumorales</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>4H-1-Benzopyran-4-ones</term><term>Arginase</term><term>Chloroquine</term><term>Morpholines</term><term>Protéines recombinantes</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Apoptose</term><term>Autophagie</term><term>Humains</term><term>Lignée cellulaire tumorale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Guangdong</li></region><settlement><li>Jiangmen</li></settlement></list><tree><country name="République populaire de Chine"><region name="Guangdong"><name sortKey="Shen, Weitao" sort="Shen, Weitao" uniqKey="Shen W" first="Weitao" last="Shen">Weitao Shen</name></region><name sortKey="Cao, Zhonglian" sort="Cao, Zhonglian" uniqKey="Cao Z" first="Zhonglian" last="Cao">Zhonglian Cao</name><name sortKey="Fan, Jiajun" sort="Fan, Jiajun" uniqKey="Fan J" first="Jiajun" last="Fan">Jiajun Fan</name><name sortKey="Fu, Xiang" sort="Fu, Xiang" uniqKey="Fu X" first="Xiang" last="Fu">Xiang Fu</name><name sortKey="Ju, Dianwen" sort="Ju, Dianwen" uniqKey="Ju D" first="Dianwen" last="Ju">Dianwen Ju</name><name sortKey="Luan, Jingyun" sort="Luan, Jingyun" uniqKey="Luan J" first="Jingyun" last="Luan">Jingyun Luan</name><name sortKey="Xu, Zhongyuan" sort="Xu, Zhongyuan" uniqKey="Xu Z" first="Zhongyuan" last="Xu">Zhongyuan Xu</name><name sortKey="Yang, Ping" sort="Yang, Ping" uniqKey="Yang P" first="Ping" last="Yang">Ping Yang</name><name sortKey="Zhang, Xuyao" sort="Zhang, Xuyao" uniqKey="Zhang X" first="Xuyao" last="Zhang">Xuyao Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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