Arctigenin Suppresses Unfolded Protein Response and Sensitizes Glucose Deprivation-Mediated Cytotoxicity of Cancer Cells
Arctigenin Suppresses Unfolded Protein Response and Sensitizes Glucose Deprivation-Mediated Cytotoxicity of Cancer Cells
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牛蒡甙元抑制未折叠蛋白反应并使葡萄糖剥夺介导的癌细胞细胞毒性变得敏感
DOI：
10.1055/s-0030-1250179
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Yu, De-Hua
中科院分区：
文献类型：
--
作者：
Sun, Shengrong;Wang, Xiong;Wang, Changhua;Nawaz, Ahmed;Wei, Wen;Li, Juanjuan;Wang, Lijun;Yu, De-Hua
未折叠蛋白反应（UPR）激活参与肿瘤生存和化疗耐药，提示以UPR通路为靶点的新的抗癌策略。牛蒡子苷元是一种天然产物，近年来发现其对葡萄糖饥饿条件下的肿瘤细胞具有选择性毒性，但其作用机制尚不清楚。在这里，我们发现，牛蒡子苷元特异性地阻断两个潜在的抗癌靶点，即葡萄糖调节蛋白-78（GRP 78）及其类似物GRP 94的转录诱导，在葡萄糖剥夺下，但不是衣霉素。其他UPR途径的激活，例如，牛蒡子苷元也能抑制葡萄糖剥夺引起的XBP-1和ATF 4。进一步的转基因实验表明，GRP 78的异位表达至少部分挽救了牛蒡子苷元/葡萄糖饥饿介导的细胞生长抑制，这表明葡萄糖饥饿下UPR抑制在牛蒡子苷元介导的细胞毒性中的因果作用。这些观察为牛蒡子苷元的作用机制带来了新的见解，并可能导致新的抗癌治疗方法的设计。
The involvement of unfolded protein response (UPR) activation in tumor survival and resistance to chemotherapies suggests a new anticancer strategy targeting UPR pathway. Arctigenin, a natural product, has been recently identified for its antitumor activity with selective toxicity against cancer cells under glucose starvation with unknown mechanism. Here we found that arctigenin specifically blocks the transcriptional induction of two potential anticancer targets, namely glucose-regulated protein-78 (GRP78) and its analog GRP94, under glucose deprivation, but not by tunicamycin. The activation of other UPR pathways, e.g., XBP-1 and ATF4, by glucose deprivation was also suppressed by arctigenin. A further transgene experiment showed that ectopic expression of GRP78 at least partially rescued arctigenin/glucose starvation-mediated cell growth inhibition, suggesting the causal role of UPR suppression in arctigenin-mediated cytotoxicity under glucose starvation. These observations bring a new insight into the mechanism of action of arctigenin and may lead to the design of new anticancer therapeutics.
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影响因子：
1.8
作者：
De-hua Yu;J. Chatterton;J. Bliesath;R. Sundaram;N. Ke;Vivian Nguy;B. Meyhack;F. Wong-Staal;
通讯作者：
De-hua Yu;J. Chatterton;J. Bliesath;R. Sundaram;N. Ke;Vivian Nguy;B. Meyhack;F. Wong-Staal;
影响因子：
4.8
作者：
Reddy, RK;Lu, J;Lee, AS
通讯作者：
Lee, AS
影响因子：
4.8
作者：
Reddy, RK;Mao, CH;Lee, AS
通讯作者：
Lee, AS
影响因子：
11.2
作者：
Romero-Ramirez, L;Cao, HB;Koong, AC
通讯作者：
Koong, AC
影响因子：
11.2
作者：
L. Romero-Ramírez;H. Cao;Daniel W. Nelson;E. Hammond;Ann-Hwee Lee;H. Yoshida;K. Mori;L. Glimcher
通讯作者：
L. Romero-Ramírez;H. Cao;Daniel W. Nelson;E. Hammond;Ann-Hwee Lee;H. Yoshida;K. Mori;L. Glimcher