title: Glycyrrhetinic acid induces G1‑phase cell cycle arrest in human non‑small cell lung cancer cells through endoplasmic reticulum stress pathway.
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.
authors.affiliation: The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Chen
authors.affiliation: The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.affiliation: The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Ma
authors.affiliation: The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Ruolin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: The First Clinical Medicine College, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016213:Cyclins / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016213:Cyclins; D004365:Drugs, Chinese Herbal; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D016160:Retinoblastoma Protein; C062477:endoplasmic reticulum glycoprotein p72; D006034:Glycyrrhetinic Acid