Glycyrrhetinic acid induces G1‑phase cell cycle arrest in human non‑small cell lung cancer cells through endoplasmic reticulum stress pathway

Zhu,Jie; Chen,Meijuan; Chen,Ning; Ma,Aizhen; Zhu,Chunyan; Zhao,Ruolin; Jiang,Miao; Zhou,Jing; Ye,Lihong; Fu,Haian; Zhang,Xu

doi:10.3892/ijo.2015.2819

Glycyrrhetinic acid induces G1‑phase cell cycle arrest in human non‑small cell lung cancer cells through endoplasmic reticulum stress pathway

Authors:
- Jie Zhu
- Meijuan Chen
- Ning Chen
- Aizhen Ma
- Chunyan Zhu
- Ruolin Zhao
- Miao Jiang
- Jing Zhou
- Lihong Ye
- Haian Fu
- Xu Zhang
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Affiliations: The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China, Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA
Published online on: January 8, 2015 https://doi.org/10.3892/ijo.2015.2819
Pages: 981-988
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Glycyrrhetinic acid (GA) is a natural compound extracted from liquorice, which is often used in traditional Chinese medicine. The purpose of the present study was to investigate the antitumor effect of GA in human non‑small cell lung cancer (NSCLC), and its underlying mechanisms in vitro. We have shown that GA suppressed the proliferation of A549 and NCI‑H460 cells. Flow cytometric analysis showed that GA arrested cell cycle in G0/G1 phase without inducing apoptosis. Western blot analysis indicated that GA mediated G1‑phase cell cycle arrest by upregulation of cyclin‑dependent kinase inhibitors (CKIs) (p18, p16, p27 and p21) and inhibition of cyclins (cyclin‑D1, ‑D3 and ‑E) and cyclin‑dependent kinases (CDKs) (CDK4, 6 and 2). GA also maintained pRb phosphorylation status, and inhibited E2F transcription factor 1 (E2F‑1) in both cell lines. GA upregulated the unfolded proteins, Bip, PERK and ERP72. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggered the unfolded protein response (UPR), which could be the mechanism by which GA inhibited cell proliferation in NSCLC cells. GA then coordinated the induction of ER chaperones, which decreased protein synthesis and induced cell cycle arrest in the G1 phase. This study provides experimental evidence to support the development of GA as a chemotherapeutic agent for NSCLC.

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