Document Type

Journal Article

Department/Unit

Department of Chemistry

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.

Publication Year

2015

Journal Title

Oncotarget

Volume number

6

Issue number

41

Publisher

Impact Journals

First Page (page number)

43911

Last Page (page number)

43926

Referreed

1

DOI

10.18632/oncotarget.6084

Link to Publisher’s Edition

http://dx.doi.org/10.18632/oncotarget.6084

Keywords

glycyrrhetinic acid, autophagy, JNK, IRE1α, protective

Large files may be slow to open. For best results, right-click and select "save as..."

Additional Files

JA-5034-28953_publisher_suppl.pdf (8557 kB)

Included in

Chemistry Commons

Share

COinS