Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth.
Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth.
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DOI：
10.1158/0008-5472.can-10-1992
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Safe S
中科院分区：
文献类型：
--
作者：
Lee SO;Abdelrahim M;Yoon K;Chintharlapalli S;Papineni S;Kim K;Wang H;Safe S
孤儿核受体TR3/Nur77(NR4A1)的激活促进细胞凋亡，抑制胰腺肿瘤生长，但其内源性功能及其失活作用尚不清楚。与非肿瘤组织相比，TR3在人胰腺肿瘤组织中高表达。SiRNA介导的TR3基因敲除或TR3拮抗剂1，1-二(3‘-吲哚)-1-(对羟基苯基)甲烷(DIM-C-pPhOH)处理胰腺癌细胞可抑制胰腺癌细胞的增殖，诱导细胞凋亡，并减少抗凋亡基因如Bcl2和Survivin的表达。Survivin抑制是通过在Survivin启动子近端富含GC的区域形成TR3-Sp1-p300DNA结合复合体来实现的。在体内给药时，DIM-C-pPhOH在胰腺癌原位模型中诱导细胞凋亡并抑制肿瘤生长，同时抑制体外观察到的相同的抗凋亡标记物。基于TR3抑制剂阻断胰腺肿瘤生长的能力，我们的结果提供了TR3作为胰腺癌化疗药物靶点的临床前验证。
Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be determined. TR3 was overexpressed in human pancreatic tumors compared to non-tumor tissue. siRNA-mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1, 1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of anti-apoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, associated with inhibition of the same anti-apoptotic markers observed in vitro. Our results offer preclinical validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors.