Inhibition of NFκB and Pancreatic Cancer Cell and Tumor Growth by Curcumin Is Dependent on Specificity Protein Down-regulation
Inhibition of NFκB and Pancreatic Cancer Cell and Tumor Growth by Curcumin Is Dependent on Specificity Protein Down-regulation
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DOI：
10.1074/jbc.m109.095240
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发表时间：
2010-08-13
影响因子：
4.8
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Jutooru, Indira;Chadalapaka, Gayathri;Safe, Stephen
姜黄素激活多种抗癌活性，导致抑制癌细胞和肿瘤生长，诱导细胞凋亡和抗血管生成反应。在本研究中，我们观察到姜黄素抑制Panc 28和L3.6pL胰腺癌细胞和荷L3.6pL细胞作为异种移植物的裸鼠的肿瘤生长。此外，姜黄素降低了p50和p65蛋白的表达和NF κ B依赖的反式激活，还降低了胰腺癌细胞中过度表达的Sp1、Sp3和Sp 4转录因子。由于Sp转录因子和NF κ B调节几个共同的基因，如细胞周期蛋白D1，生存素和血管内皮生长因子，有助于癌症表型，我们也研究了Sp和NF κ B转录因子之间的相互作用。通过RNA干扰敲低Sp1、Sp3和Sp 4的结果表明，p50和p65都是Sp-regulated基因，姜黄素对组成型或肿瘤坏死因子诱导的NF κ B B的抑制依赖于该化合物对Sp1、Sp3和Sp 4蛋白的下调。姜黄素还降低胰腺癌细胞中的线粒体膜电位并诱导活性氧，并且该途径是下调这些细胞中的Sp蛋白所需的，表明姜黄素的细胞毒性作用对其抗癌活性很重要。
Curcumin activates diverse anticancer activities that lead to inhibition of cancer cell and tumor growth, induction of apoptosis, and antiangiogenic responses. In this study, we observed that curcumin inhibits Panc28 and L3.6pL pancreatic cancer cell and tumor growth in nude mice bearing L3.6pL cells as xenografts. In addition, curcumin decreased expression of p50 and p65 proteins and NF kappa B-dependent transactivation and also decreased Sp1, Sp3, and Sp4 transcription factors that are over-expressed in pancreatic cancer cells. Because both Sp transcription factors and NF kappa B regulate several common genes such as cyclin D1, survivin, and vascular endothelial growth factor that contribute to the cancer phenotype, we also investigated interactions between Sp and NF kappa B transcription factors. Results of Sp1, Sp3, and Sp4 knockdown by RNA interference demonstrate that both p50 and p65 are Sp-regulated genes and that inhibition of constitutive or tumor necrosis factor-induced NF kappa B by curcumin is dependent on down-regulation of Sp1, Sp3, and Sp4 proteins by this compound. Curcumin also decreased mitochondrial membrane potential and induced reactive oxygen species in pancreatic cancer cells, and this pathway is required for down-regulation of Sp proteins in these cells, demonstrating that the mitochondriotoxic effects of curcumin are important for its anticancer activities.