RETRACTED ARTICLE: Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cγ1-, Ca2+-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells
Authors: Yeon Ju Jeong
Wonchae Choe
Kyung-Sik Yoon
Eui-Ju Yeo
Joohun Ha
A-Young Choi
Sung Soo Kim
Insug Kang
Jang Hyun Youn
Ji Hyun Choi
Keun-Young Hwang
Journal: APOPTOSIS (2014)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Licochalcone A; apoptosis; ER stress; caspase; CHOP
Affiliations: Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 130-701, Republic of Korea.

Abstract:  Licochalcone A (LicA), an estrogenic flavonoid, induces apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of LicA were investigated in HepG2 human hepatocellular carcinoma cells. LicA induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by CHOP knockdown or treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced LicA-induced cell death. LicA also induced reactive oxygen species (ROS) accumulation and the anti-oxidant N-acetylcysteine reduced LicA-induced cell death and CHOP expression. In addition, LicA increased the levels of cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate (an antagonist of inositol 1,4,5-trisphosphate receptor) and BAPTA-AM (an intracellular Ca(2+) chelator). 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited LicA-induced cell death. Interestingly, LicA induced phosphorylation of phospholipase Cγ1 (PLCγ1) and inhibition of PLCγ1 reduced cell death and ER stress. Moreover, the multi-targeted receptor tyrosine kinase inhibitors, sorafenib and sunitinib, reduced LicA-induced cell death, ER stress, and cytosolic Ca(2+) and ROS accumulation. Finally, LicA induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and c-Met receptor and inhibition of both receptors by co-transfection with VEGFR2 and c-Met siRNAs reversed LicA-induced cell death, Ca(2+) increase, and CHOP expression. Taken together, these findings suggest that induction of ER stress via a PLCγ1-, Ca(2+)-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells. 

Retracted: No

PubPeer comments:
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 Corrected [2 November 2018] . Retracted [13 November 2021] . -------------------------------- The Editors-in-Chief have retracted this article [1] because there are duplications in some of the figures: In Fig. 6B, the u03b2-actin bands of this gel are repeated three times, therefore all regulations of CHOP, ATF6u03b1(p90), and caspase-4C and P-eIF2u03b1 by sunitinib and sorafenib are inconclusive. Additionally, the row of u03b2-actin bands of Fig. 1E has been used in Fig. 3E as the row of eIF2u03b1. Therefore the conclusions of Fig. 3 or those of Fig. 1, or possibly both, may be incorrect. The conclusions of this article are therefore unreliable. Please note that Figs. 1D, 5D and 7D have been previously corrected [2]. A written response from Dr. Insug Kang and Dr. Eui-Ju Yeo, representing all authors, confirmed that there were mistakes and errors in the article. Drs. Kang and Yeo expressed that they do not agree to this retraction. ,