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phospholipase Cγ1-, Ca2+-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells (Retracted Article)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phospholipase Cγ1-, Ca2+-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells (Retracted Article)
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DOI：
10.1007/s10495-013-0955-y
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发表时间：
2014-04-01
期刊：
影响因子：
7.2
通讯作者：
Kang, Insug
中科院分区：
文献类型：
--
作者：
Choi, A-Young;Choi, Ji Hyun;Kang, Insug
甘草查尔酮A（LicA）是一种雌激素类黄酮，可诱导多种类型的癌细胞凋亡。在这项研究中，在HepG2人肝癌细胞中研究了LicA抗癌作用的分子机制。LicA诱导凋亡性细胞死亡，半胱天冬酶-4、-9和-3的活化，以及内质网（ER）应激相关蛋白（包括C/EBP同源蛋白（CHOP））的表达。通过CHOP敲低或用ER应激抑制剂salubrinal和4-苯基丁酸处理来抑制ER应激，减少了LicA诱导的细胞死亡。LicA还诱导活性氧（ROS）的积累和抗氧化剂N-乙酰半胱氨酸减少LicA诱导的细胞死亡和CHOP的表达。此外，LicA增加胞浆Ca~（2+）水平，这被2-氨基乙氧基二苯基硼酸酯（1，4，5-三磷酸肌醇受体的拮抗剂）和BAPTA-AM（胞内Ca~（2+）螯合剂）阻断。2-氨基乙氧基二苯基硼酸酯和BAPTA-AM抑制LicA诱导的细胞死亡。有趣的是，LicA诱导磷脂酶C γ 1（PLC γ 1）的磷酸化，并抑制PLC γ 1减少细胞死亡和ER应激。此外，多靶向受体酪氨酸激酶抑制剂索拉非尼和舒尼替尼减少了LicA诱导的细胞死亡、ER应激以及胞质Ca 2+和ROS积累。最后，LicA诱导血管内皮生长因子受体2（VEGFR2）和c-Met受体的磷酸化，并通过VEGFR2和c-Met siRNA共转染抑制这两种受体，逆转了LicA诱导的细胞死亡、Ca2+增加和CHOP表达。总之，这些发现表明，通过PLC γ 1-，Ca2 +-和ROS依赖性途径诱导ER应激可能是LicA诱导HepG2肝癌细胞凋亡的重要机制。
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 C gamma 1 (PLC gamma 1) and inhibition of PLC gamma 1 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 PLC gamma 1-, Ca2+-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells.