Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB.
Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB.
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DOI：
10.1002/ijc.24628
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发表时间：
2009-11-15
影响因子：
6.4
通讯作者：
Mukhtar, Hasan
中科院分区：
文献类型：
--
作者：
Murtaza, Imtiyaz;Adhami, Vaqar Mustafa;Bin Hafeez, Bilal;Saleem, Mohammad;Mukhtar, Hasan
肿瘤坏死因子（TNF）受体超家族的死亡受体参与胰腺癌（PaC）细胞中核因子κ B（NF-κB）的组成性激活。在这项研究中，我们证明，非瑟酮，一种天然黄酮类化合物，诱导凋亡，并通过抑制DR 3介导的NF-κB激活抑制耐药PaC AsPC-1细胞的侵袭。非瑟酮处理导致PaC细胞生长和细胞增殖的剂量依赖性抑制，同时诱导细胞凋亡。cDNA阵列分析显示，非瑟酮在转录水平上调节超过20个基因的表达，观察到DR 3表达的最大降低和观察到NF-κB抑制剂IκBα表达水平的平行增加。发现在PaC细胞中DR 3的下调下调活化的pNF-κB/p65、pIKK B α/β激酶（pIKK's）、MMP 9和XIAP，其主要赋予PaC中的化学抗性。免疫印迹和EMSA分析显示，非瑟酮处理后pNF-κB和NF-κB DNA结合活性分别显著降低，NF-κB启动子活性适度降低，MMP 9启动子活性显著降低。重要的是，与这些发现一致，我们进一步发现通过RNA干扰瞬时下调DR 3显著增强非瑟酮诱导的细胞增殖、细胞侵袭和凋亡的变化，同时降低pNF-κB、pIKKα/β、MMP 9、XIAP和NF-κB DNA结合活性。用胞外结构域阻断抗体阻断DR 3受体表现出类似的效果。这些数据提供的证据表明，非瑟酮可以提供治疗胰腺癌或作为常规治疗方案的辅助生物学原理。
Death receptors of the tumor necrosis factor (TNF) receptor super family have been implicated in constitutive activation of Nuclear Factor kappa B (NF-κB) in pancreatic cancer (PaC) cells. In this study we demonstrate that fisetin, a natural flavonoid, induces apoptosis and inhibits invasion of chemoresistant PaC AsPC-1 cells through suppression of DR3 mediated NF-κB activation. Fisetin treatment resulted in dose-dependent inhibition of PaC cell growth and cell proliferation with concomitant induction of apoptosis. A cDNA array analysis revealed that fisetin modulates expression of more than 20 genes at transcription level with maximum decrease observed in DR3 expression and a parallel increase observed in the expression levels of IκBα, an NF-κB inhibitor. Down-regulation of DR3 in PaC cells was found to down regulate activated pNF-κB/p65, pIkBα/β kinases (pIKK’s), MMP9 and XIAP that mostly impart chemoresistance in PaC. Immunoblotting and EMSA analysis showed a marked decrease in pNF-κB and NF-κB DNA binding activity respectively with modest decrease in NF-κB promoter activity and significant decrease in MMP9 promoter activity with fisetin treatment. Importantly, consistent with these findings, we further found that transient down-regulation of DR3 by RNA interference significantly augmented fisetin induced changes in cell proliferation, cell invasion and apoptosis paralleled with decrease in pNF-κB, pIKKα/β, MMP9, XIAP and NF-κB DNA binding activity. Blocking of DR3 receptor with an extra cellular domain blocking antibody demonstrated similar effects. These data provide evidence that fisetin could provide a biological rationale for treatment of pancreatic cancer or as an adjuvant with conventional therapeutic regimens.
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