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EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells.

Identifieur interne : 001473 ( Main/Exploration ); précédent : 001472; suivant : 001474

EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells.

Auteurs : Weidong Han [République populaire de Chine] ; Hongming Pan ; Yan Chen ; Jie Sun ; Yanshan Wang ; Jing Li ; Weiting Ge ; Lifeng Feng ; Xiaoying Lin ; Xiaojia Wang ; Xian Wang ; Hongchuan Jin

Source :

RBID : pubmed:21655094

Descripteurs français

English descriptors

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.

DOI: 10.1371/journal.pone.0018691
PubMed: 21655094


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<term>Autophagy-Related Protein 7</term>
<term>Blotting, Western</term>
<term>Carcinoma, Non-Small-Cell Lung (genetics)</term>
<term>Carcinoma, Non-Small-Cell Lung (metabolism)</term>
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<term>ErbB Receptors (metabolism)</term>
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<term>Lung Neoplasms (metabolism)</term>
<term>Lung Neoplasms (pathology)</term>
<term>Lysosomes (drug effects)</term>
<term>Lysosomes (metabolism)</term>
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<term>Microscopy, Electron</term>
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<term>Microtubule-Associated Proteins (metabolism)</term>
<term>Phagosomes (drug effects)</term>
<term>Phagosomes (metabolism)</term>
<term>Phagosomes (ultrastructure)</term>
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<term>Lysosomes (ultrastructure)</term>
<term>Microscopie confocale</term>
<term>Microscopie électronique</term>
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<term>Phagosomes (métabolisme)</term>
<term>Phagosomes (ultrastructure)</term>
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<term>Protéines associées aux microtubules (métabolisme)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Quinazolines (pharmacologie)</term>
<term>Relation dose-effet des médicaments</term>
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<term>Tumeurs du poumon</term>
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<term>Chlorhydrate d'erlotinib</term>
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<term>Interférence par ARN</term>
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<front>
<div type="abstract" xml:lang="en">Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.</div>
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