AZD9291 promotes autophagy and inhibits PI3K/Akt pathway in NSCLC cancer cells.
Identifieur interne : 000B23 ( Main/Exploration ); précédent : 000B22; suivant : 000B24AZD9291 promotes autophagy and inhibits PI3K/Akt pathway in NSCLC cancer cells.
Auteurs : Zhirui Zhang [République populaire de Chine] ; Mengxiao Zhang [République populaire de Chine] ; Hao Liu [République populaire de Chine] ; Wu Yin [République populaire de Chine]Source :
- Journal of cellular biochemistry [ 1097-4644 ] ; 2019.
Descripteurs français
- KwdFr :
- Acrylamides (pharmacologie), Animaux, Autophagie (), Carcinome pulmonaire non à petites cellules (anatomopathologie), Carcinome pulmonaire non à petites cellules (métabolisme), Cellules A549, Charge tumorale (), Chloroquine (pharmacologie), Dérivés de l'aniline (pharmacologie), Humains, Phosphatidylinositol 3-kinases (métabolisme), Protéines associées aux microtubules (métabolisme), Protéines de liaison à l'ARN (métabolisme), Protéines proto-oncogènes c-akt (génétique), Protéines proto-oncogènes c-akt (métabolisme), Récepteurs ErbB (métabolisme), Souris, Souris nude, Survie cellulaire (), Techniques de knock-down de gènes, Tests d'activité antitumorale sur modèle de xénogreffe, Transduction du signal (), Transfection, Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (métabolisme).
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- génétique : Protéines proto-oncogènes c-akt.
- métabolisme : Carcinome pulmonaire non à petites cellules, Phosphatidylinositol 3-kinases, Protéines associées aux microtubules, Protéines de liaison à l'ARN, Protéines proto-oncogènes c-akt, Récepteurs ErbB, Tumeurs du poumon.
- pharmacologie : Acrylamides, Chloroquine, Dérivés de l'aniline.
- Animaux, Autophagie, Cellules A549, Charge tumorale, Humains, Souris, Souris nude, Survie cellulaire, Techniques de knock-down de gènes, Tests d'activité antitumorale sur modèle de xénogreffe, Transduction du signal, Transfection.
English descriptors
- KwdEn :
- A549 Cells, Acrylamides (pharmacology), Aniline Compounds (pharmacology), Animals, Autophagy (drug effects), Carcinoma, Non-Small-Cell Lung (metabolism), Carcinoma, Non-Small-Cell Lung (pathology), Cell Survival (drug effects), Chloroquine (pharmacology), ErbB Receptors (metabolism), Gene Knockdown Techniques, Humans, Lung Neoplasms (metabolism), Lung Neoplasms (pathology), Mice, Mice, Nude, Microtubule-Associated Proteins (metabolism), Phosphatidylinositol 3-Kinases (metabolism), Proto-Oncogene Proteins c-akt (genetics), Proto-Oncogene Proteins c-akt (metabolism), RNA-Binding Proteins (metabolism), Signal Transduction (drug effects), Transfection, Tumor Burden (drug effects), Xenograft Model Antitumor Assays.
- MESH :
- chemical , genetics : Proto-Oncogene Proteins c-akt.
- chemical , metabolism : ErbB Receptors, Microtubule-Associated Proteins, Proto-Oncogene Proteins c-akt, RNA-Binding Proteins.
- chemical , pharmacology : Acrylamides, Aniline Compounds, Chloroquine.
- drug effects : Autophagy, Cell Survival, Signal Transduction, Tumor Burden.
- metabolism : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Phosphatidylinositol 3-Kinases.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- A549 Cells, Animals, Gene Knockdown Techniques, Humans, Mice, Mice, Nude, Transfection, Xenograft Model Antitumor Assays.
Abstract
AZD9291, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is highly selective against EGFR T790M-mutant non-small cell lung cancer (NSCLC). On investigating the growth inhibitory effects of AZD9291 on NSCLC and the underlying mechanism, we found that AZD9291 can trigger autophagy-mediated cell death in both A549 and H1975 cells by increasing the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3) and decreasing the expression of p62. In the presence of the autophagy inhibitor chloroquine, the AZD9291-induced increase in LC3 level was further augmented. AZD9291 decreased the levels of phosphoinositide-3 kinase (PI3K), protein kinase B (Akt), and phosphorylated Akt. AZD9291-induced cell death was enhanced by Akt knockdown, and the levels of both EGFR and phosphorylated EGFR were decreased by AZD9291. AZD9291 was also found to significantly suppress the tumor growth in H1975 xenograft nude mice. Thus, AZD9291 was found to induce autophagy, decrease in EGFR levels, and show a strong inhibitory effect on NSCLC both in vitro and in vivo. Furthermore, the PI3K/Akt signaling pathway was found to play a critical role in AZD9291-induced cell death.
DOI: 10.1002/jcb.27434
PubMed: 30145802
Affiliations:
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Le document en format XML
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uniqKey="Zhang M" first="Mengxiao" last="Zhang">Mengxiao Zhang</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui</wicri:regionArea><wicri:noRegion>Anhui</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Hao" sort="Liu, Hao" uniqKey="Liu H" first="Hao" last="Liu">Hao Liu</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui</wicri:regionArea><wicri:noRegion>Anhui</wicri:noRegion></affiliation></author><author><name sortKey="Yin, Wu" sort="Yin, Wu" uniqKey="Yin W" first="Wu" last="Yin">Wu Yin</name><affiliation wicri:level="1"><nlm:affiliation>The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing</wicri:regionArea><wicri:noRegion>Nanjing</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of cellular biochemistry</title><idno type="eISSN">1097-4644</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>A549 Cells</term><term>Acrylamides (pharmacology)</term><term>Aniline Compounds (pharmacology)</term><term>Animals</term><term>Autophagy (drug effects)</term><term>Carcinoma, Non-Small-Cell Lung (metabolism)</term><term>Carcinoma, Non-Small-Cell Lung (pathology)</term><term>Cell Survival (drug effects)</term><term>Chloroquine (pharmacology)</term><term>ErbB Receptors (metabolism)</term><term>Gene Knockdown Techniques</term><term>Humans</term><term>Lung Neoplasms (metabolism)</term><term>Lung Neoplasms (pathology)</term><term>Mice</term><term>Mice, Nude</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Phosphatidylinositol 3-Kinases (metabolism)</term><term>Proto-Oncogene Proteins c-akt (genetics)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>RNA-Binding Proteins (metabolism)</term><term>Signal Transduction (drug effects)</term><term>Transfection</term><term>Tumor Burden (drug effects)</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acrylamides (pharmacologie)</term><term>Animaux</term><term>Autophagie ()</term><term>Carcinome pulmonaire non à petites cellules (anatomopathologie)</term><term>Carcinome pulmonaire non à petites cellules (métabolisme)</term><term>Cellules A549</term><term>Charge tumorale ()</term><term>Chloroquine (pharmacologie)</term><term>Dérivés de l'aniline (pharmacologie)</term><term>Humains</term><term>Phosphatidylinositol 3-kinases (métabolisme)</term><term>Protéines associées aux microtubules (métabolisme)</term><term>Protéines de liaison à l'ARN (métabolisme)</term><term>Protéines proto-oncogènes c-akt (génétique)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Récepteurs ErbB (métabolisme)</term><term>Souris</term><term>Souris nude</term><term>Survie cellulaire ()</term><term>Techniques de knock-down de gènes</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Transduction du signal ()</term><term>Transfection</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Tumeurs du poumon (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>ErbB Receptors</term><term>Microtubule-Associated Proteins</term><term>Proto-Oncogene Proteins c-akt</term><term>RNA-Binding Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Acrylamides</term><term>Aniline Compounds</term><term>Chloroquine</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>Autophagy</term><term>Cell Survival</term><term>Signal Transduction</term><term>Tumor Burden</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines proto-oncogènes c-akt</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term><term>Phosphatidylinositol 3-Kinases</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Phosphatidylinositol 3-kinases</term><term>Protéines associées aux microtubules</term><term>Protéines de liaison à l'ARN</term><term>Protéines proto-oncogènes c-akt</term><term>Récepteurs ErbB</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>Acrylamides</term><term>Chloroquine</term><term>Dérivés de l'aniline</term></keywords><keywords scheme="MESH" xml:lang="en"><term>A549 Cells</term><term>Animals</term><term>Gene Knockdown Techniques</term><term>Humans</term><term>Mice</term><term>Mice, Nude</term><term>Transfection</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Autophagie</term><term>Cellules A549</term><term>Charge tumorale</term><term>Humains</term><term>Souris</term><term>Souris nude</term><term>Survie cellulaire</term><term>Techniques de knock-down de gènes</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Transduction du signal</term><term>Transfection</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">AZD9291, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is highly selective against EGFR T790M-mutant non-small cell lung cancer (NSCLC). On investigating the growth inhibitory effects of AZD9291 on NSCLC and the underlying mechanism, we found that AZD9291 can trigger autophagy-mediated cell death in both A549 and H1975 cells by increasing the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3) and decreasing the expression of p62. In the presence of the autophagy inhibitor chloroquine, the AZD9291-induced increase in LC3 level was further augmented. AZD9291 decreased the levels of phosphoinositide-3 kinase (PI3K), protein kinase B (Akt), and phosphorylated Akt. AZD9291-induced cell death was enhanced by Akt knockdown, and the levels of both EGFR and phosphorylated EGFR were decreased by AZD9291. AZD9291 was also found to significantly suppress the tumor growth in H1975 xenograft nude mice. Thus, AZD9291 was found to induce autophagy, decrease in EGFR levels, and show a strong inhibitory effect on NSCLC both in vitro and in vivo. Furthermore, the PI3K/Akt signaling pathway was found to play a critical role in AZD9291-induced cell death.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhang, Zhirui" sort="Zhang, Zhirui" uniqKey="Zhang Z" first="Zhirui" last="Zhang">Zhirui Zhang</name></noRegion><name sortKey="Liu, Hao" sort="Liu, Hao" uniqKey="Liu H" first="Hao" last="Liu">Hao Liu</name><name sortKey="Yin, Wu" sort="Yin, Wu" uniqKey="Yin W" first="Wu" last="Yin">Wu Yin</name><name sortKey="Zhang, Mengxiao" sort="Zhang, Mengxiao" uniqKey="Zhang M" first="Mengxiao" last="Zhang">Mengxiao Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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