Inactivation of the orphan nuclear receptor NR4A1 contributes to apoptosis induction by fangchinoline in pancreatic cancer cells
Inactivation of the orphan nuclear receptor NR4A1 contributes to apoptosis induction by fangchinoline in pancreatic cancer cells
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DOI：
10.1016/j.taap.2017.07.017
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发表时间：
2017-10-01
影响因子：
3.8
通讯作者：
Lee, Syng-Ook
中科院分区：
文献类型：
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作者：
Lee, Hyo-Seon;Safe, Stephen;Lee, Syng-Ook
先前的研究表明，孤儿核受体NR4A1在人胰腺癌中过表达，拮抗该受体可促进细胞凋亡，抑制胰腺癌细胞和肿瘤生长。在本研究中，我们确定防己内酯是一种新的核NR4A1失活剂，并证明防己内酯通过依赖于NR4A1的促凋亡途径部分地抑制人胰腺癌细胞的增殖和诱导细胞凋亡。它通过抑制Sp1介导的转录减少抗凋亡蛋白Survivin的表达，并诱导胰腺癌细胞氧化应激介导的内质网(ER)应激。这些结果表明，抑制NR4A1介导的转录活性参与了防己甲素的抗癌作用，并且防己甲酚代表了一类针对胰腺癌中过度表达的NR4A1的新型机制抗癌剂。(C)2017 Elsevier Inc.保留所有权利。
Previous studies have demonstrated that the orphan nuclear receptor NR4A1 is overexpressed in human pancreatic cancer and antagonizing this receptor promotes apoptosis and inhibits pancreatic cancer cells and tumor growth. In the present study, we identified fangchinoline, a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, as a new inactivator of nuclear NR4A1 and demonstrated that fangchinoline inhibits cell proliferation and induces apoptosis, in part, via the NR4A1-dependent pro-apoptotic pathways in human pancreatic cancer cells. It decreased expression of the antiapoptotic protein survivin by inhibiting Sp1-mediated transcription and induced oxidative stress-mediated endoplasmic reticulum (ER) stress in pancreatic cancer cells. These results suggest that inhibition of NR4A1-mediated transcriptional activity was involved in the anticancer effects of fangchinoline, and fangchinoline represents a novel class of mechanism-based anticancer agents targeting NR4A1 that is overexpressed in pancreatic cancer. (C) 2017 Elsevier Inc. All rights reserved.