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
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- 作者：A-Young Choi (1)
Ji Hyun Choi (1)
Keun-Young Hwang (1)
Yeon Ju Jeong (1)
Wonchae Choe (1)
Kyung-Sik Yoon (1)
Joohun Ha (1)
Sung Soo Kim (1)
Jang Hyun Youn (1) (2)
Eui-Ju Yeo (3)
Insug Kang (1) - 关键词：Apoptosis ; Calcium ; ER stress ; HepG2 cells ; Licochalcone A ; PLCγ1
- 刊名：Apoptosis
- 出版年：2014
- 出版时间：April 2014
- 年：2014
- 卷：19
- 期：4
- 页码：682-697
- 全文大小：3,257 KB
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Ji Hyun Choi (1)
Keun-Young Hwang (1)
Yeon Ju Jeong (1)
Wonchae Choe (1)
Kyung-Sik Yoon (1)
Joohun Ha (1)
Sung Soo Kim (1)
Jang Hyun Youn (1) (2)
Eui-Ju Yeo (3)
Insug Kang (1)
1. 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
2. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089-9142, USA
3. Department of Biochemistry, School of Medicine, Gachon University, Inchon, 406-799, Republic of Korea - ISSN：1573-675X
文摘
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 Ca2+, which was blocked by 2-aminoethoxydiphenyl borate (an antagonist of inositol 1,4,5-trisphosphate receptor) and BAPTA-AM (an intracellular Ca2+ 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 Ca2+ 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, Ca2+ increase, and CHOP expression. Taken together, these findings suggest that induction of ER stress via a PLCγ1-, Ca2+-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells.