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Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1 alpha-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells
Zheng-Hai Tang1; Le-Le Zhang1; Ting Li1; Jia-Hong Lu1; Dik-Lung Ma2; Chung-Hang Leung1; Xiu-Ping Chen1; Hu-Lin Jiang3; Yi-Tao Wang1; Jin-Jian Lu1
2015-12-22
Source PublicationONCOTARGET
ISSN1949-2553
Volume6Issue:41Pages:43911-43926
Abstract

Glycerrhetinic acid (GA), one of the main bioactive constituents of Glycyrrhiza uralensis Fisch, exerts anti-cancer effects on various cancer cells. We confirmed that GA inhibited cell proliferation and induced apoptosis in non-small cell lung cancer A549 and NCI-H1299 cells. GA also induced expression of autophagy marker phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and punta formation of green fluorescent protein microtubule-associated protein light-chain 3. We further proved that expression of GA-increased autophagy marker was attributed to activation instead of suppression of autophagic flux. The c-jun N-terminal kinase (JNK) pathway was activated after incubation with GA. Pretreatment with the JNK inhibitor SP600125 or silencing of the JNK pathway by siRNA of JNK or c-jun decreased GA-induced autophagy. The endoplasmic reticulum (ER) stress responses were also apparently stimulated by GA by triggering the inositol-requiring enzyme 1α (IRE1α) pathway. The GA-induced JNK pathway activation and autophagy were decreased by IRE1α knockdown, and inhibition of autophagy or the JNK cascade increased GA-stimulated IRE1α expression. In addition, GA-induced cell proliferative inhibition and apoptosis were increased by inhibition of autophagy or the JNK pathway. Our study was the first to demonstrate that GA induces cytoprotective autophagy in non-small cell lung cancer cells by activating the IRE1α-JNK/c-jun pathway. The combined treatment of autophagy inhibitors markedly enhances the anti-neoplasmic activity of GA. Such combination shows potential as a strategy for GA or GA-contained prescriptions in cancer therapy.

KeywordGlycyrrhetinic Acid Autophagy Jnk Ire1 Alpha Protective
DOI10.18632/oncotarget.6084
Language英语
WOS Research AreaOncology ; Cell Biology
WOS SubjectOncology ; Cell Biology
WOS IDWOS:000369908400056
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Cited Times [WOS]:31   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorJin-Jian Lu
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
3.State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zheng-Hai Tang,Le-Le Zhang,Ting Li,et al. Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1 alpha-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells[J]. ONCOTARGET,2015,6(41):43911-43926.
APA Zheng-Hai Tang.,Le-Le Zhang.,Ting Li.,Jia-Hong Lu.,Dik-Lung Ma.,...&Jin-Jian Lu.(2015).Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1 alpha-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells.ONCOTARGET,6(41),43911-43926.
MLA Zheng-Hai Tang,et al."Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1 alpha-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells".ONCOTARGET 6.41(2015):43911-43926.
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