B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy.
B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy.
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B5 是一种硫氧还蛋白还原酶抑制剂，通过抑制硫氧还蛋白系统、破坏线粒体依赖性途径并触发自噬来诱导人宫颈癌细胞凋亡
DOI：
10.18632/oncotarget.5132
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发表时间：
2015-10-13
期刊：
影响因子：
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通讯作者：
Chen HY
中科院分区：
文献类型：
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作者：
Shao FY;Du ZY;Ma DL;Chen WB;Fu WY;Ruan BB;Rui W;Zhang JX;Wang S;Wong NS;Xiao H;Li MM;Liu X;Liu QY;Zhou XD;Yan HZ;Wang YF;Chen CY;Liu Z;Chen HY
人工合成的姜黄素类似物B5是硫氧还蛋白还原酶(TrxR)的有效抑制剂，具有潜在的抗癌作用。B5作为抗癌药物的分子机制尚不完全清楚。在这项研究中，我们报道了B5诱导两种人宫颈癌细胞CaSki和SIHA的凋亡，其证据是XIAP下调，caspase激活和PARP裂解。线粒体途径参与了B5诱导的细胞凋亡，表现为线粒体膜电位的降低和促凋亡蛋白Bcl2家族蛋白表达的增加。在B5处理的细胞中，TrxR活性明显受到抑制，同时伴随着氧化的硫氧还蛋白的积累，活性氧物种(ROS)的形成，以及ASK1及其下游调控靶点p38/JNK的激活。N-乙酰-L-半胱氨酸可显著抑制B5诱导的细胞凋亡。对B5处理的细胞进行显微镜检查，发现细胞质中的空泡增多。随后，通过丫啶橙细胞染色、LC3-II的积累和自噬通量的测量，证实了B5激活细胞自噬的能力。与B5诱导的细胞凋亡不同，B5诱导的自噬不是ROS介导的，而是AKT和AMPK信号通路的作用。在SIHA细胞中，自噬促进了B5诱导的细胞凋亡，但在CaSki细胞中没有。这些数据表明，B5的抗癌作用是由控制氧化还原稳态、细胞凋亡和自噬的细胞机制之间的复杂相互作用所介导的。
The synthetic curcumin analog B5 is a potent inhibitor of thioredoxin reductase (TrxR) that has potential anticancer effects. The molecular mechanism underlying B5 as an anticancer agent is not yet fully understood. In this study, we report that B5 induces apoptosis in two human cervical cancer cell lines, CaSki and SiHa, as evidenced by the downregulation of XIAP, activation of caspases and cleavage of PARP. The involvement of the mitochondrial pathway in B5-induced apoptosis was suggested by the dissipation of mitochondrial membrane potential and increased expression of pro-apoptotic Bcl-2 family proteins. In B5-treated cells, TrxR activity was markedly inhibited with concomitant accumulation of oxidized thioredoxin, increased formation of reactive oxygen species (ROS), and activation of ASK1 and its downstream regulatory target p38/JNK. B5-induced apoptosis was significantly inhibited in the presence of N-acetyl-l-cysteine. Microscopic examination of B5-treated cells revealed increased presence of cytoplasmic vacuoles. The ability of B5 to activate autophagy in cells was subsequently confirmed by cell staining with acridine orange, accumulation of LC3-II, and measurement of autophagic flux. Unlike B5-induced apoptosis, autophagy induced by B5 is not ROS-mediated but a role for the AKT and AMPK signaling pathways is implied. In SiHa cells but not CaSki cells, B5-induced apoptosis was promoted by autophagy. These data suggest that the anticarcinogenic effects of B5 is mediated by complex interplay between cellular mechanisms governing redox homeostasis, apoptosis and autophagy.