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Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1?-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells.


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 1? (IRE1?) pathway. The GA-induced JNK pathway activation and autophagy were decreased by IRE1? knockdown, and inhibition of autophagy or the JNK cascade increased GA-stimulated IRE1? 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 IRE1?-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.

SUBMITTER: Tang ZH 

PROVIDER: S-EPMC4791276 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1α-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells.

Tang Zheng-Hai ZH   Zhang Le-Le LL   Li Ting T   Lu Jia-Hong JH   Ma Dik-Lung DL   Leung Chung-Hang CH   Chen Xiu-Ping XP   Jiang Hu-Lin HL   Wang Yi-Tao YT   Lu Jin-Jian JJ  

Oncotarget 20151201 41


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-ch  ...[more]

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