Quercetin induces tongue squamous cell carcinoma cell apoptosis via the JNK activation-regulated ERK/GSK-3α/β-mediated mitochondria-dependent apoptotic signaling pathway.

Content Provider	Europe PMC
Author	Huang, Chun-Fa Liu, Shing-Hwa Ho, Tsung-Jung Lee, Kuan-I Fang, Kai-Min Lo, Wu-Chia Liu, Jui-Ming Wu, Chin-Ching Su, Chin-Chuan
Copyright Year	2022
Abstract	Tongue squamous cell carcinoma (SCC) is a most common type of oral cancer. Due to its highly invasive nature and poor survival rate, the development of effective pharmacological therapeutic agents is urgently required. Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a polyphenolic flavonoid found in plants and is an active component of Chinese herbal medicine. The present study investigated the pharmacological effects and possible mechanisms of quercetin on apoptosis of the tongue SCC-derived SAS cell line. Following treatment with quercetin, cell viability was assessed via the MTT assay. Apoptotic and necrotic cells, mitochondrial transmembrane potential and caspase-3/7 activity were analyzed via flow cytometric analyses. A caspase-3 activity assay kit was used to detect the expression of caspase-3 activity. Western blot analysis was performed to examine the expression levels of proteins associated with the MAPKs, AMPKα, GSK3-α/β and caspase-related signaling pathways. The results revealed that quercetin induced morphological alterations and decreased the viability of SAS cells. Quercetin also increased apoptosis-related Annexin V-FITC fluorescence and caspase-3 activity, and induced mitochondria-dependent apoptotic signals, including a decrease in mitochondrial transmembrane potential and Bcl-2 protein expression, and an increase in cytosolic cytochrome c, Bax, Bak, cleaved caspase-3, cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase protein expression. Furthermore, quercetin significantly increased the protein expression levels of phosphorylated (p)-ERK, p-JNK1/2 and p-GSK3-α/β, but not p-p38 or p-AMPKα in SAS cells. Pretreatment with the pharmacological JNK inhibitor SP600125 effectively reduced the quercetin-induced apoptosis-related signals, as well as p-ERK1/2 and p-GSK3-α/β protein expression. Both ERK1/2 and GSK3-α/β inhibitors, PD98059 and LiCl, respectively, could significantly prevent the quercetin-induced phosphorylation of ERK1/2 and GSK3-α/β, but not JNK activation. Taken together, these results suggested that quercetin may induce tongue SCC cell apoptosis via the JNK-activation-regulated ERK1/2 and GSK3-α/β-mediated mitochondria-dependent apoptotic signaling pathway.
ISSN	17921074
Journal	Oncology Letters
Volume Number	23
PubMed Central reference number	PMC8771640
Issue Number	3
PubMed reference number	35111247
e-ISSN	17921082
DOI	10.3892/ol.2022.13198
Language	English
Publisher	D.A. Spandidos
Publisher Date	2022-01-11
Access Restriction	Open
Rights License	This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Copyright: © Huang et al.
Subject Keyword	tongue squamous cell carcinoma quercetin apoptosis mitochondria JNK/ERK/GSK3
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology