Curcumin decreases specificity protein expression in bladder cancer cells.
Curcumin decreases specificity protein expression in bladder cancer cells.
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DOI：
10.1158/0008-5472.can-07-6805
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发表时间：
2008-07-01
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：
Chadalapaka G;Jutooru I;Chintharlapalli S;Papineni S;Smith R 3rd;Li X;Safe S
姜黄素是姜黄的活性成分，这种多酚化合物作为一种调节多种途径和基因的抗癌药物已被广泛研究。在这项研究中，10 - 25 μM姜黄素抑制253 JB-V和KU 7膀胱癌细胞生长，并伴随着诱导凋亡和降低促凋亡蛋白生存素和血管生成蛋白血管内皮生长因子（VEGF）和VEGF受体1（VEGF 1）的表达。由于生存素，VEGF和VEGFR 1的表达依赖于特异性蛋白（Sp）转录因子，我们还研究了姜黄素对Sp蛋白表达的影响，作为该化合物的凋亡和抗血管生成活性的潜在机制。结果显示，姜黄素诱导253 JB-V和KU 7细胞中Sp1、Sp3和Sp 4的蛋白酶体依赖性下调。此外，使用RNA干扰Sp1、Sp3和Sp 4的小抑制RNA，我们观察到姜黄素依赖性抑制核因子κB（NFκB）依赖性基因，如bcl-2、生存素和细胞周期蛋白D1，也部分是由于Sp蛋白的丢失。姜黄素也降低膀胱肿瘤的生长在无胸腺裸鼠携带KU 7细胞作为异种移植物，这是伴随着减少的Sp1，Sp3和Sp 4蛋白水平的肿瘤。这些结果首次证明姜黄素作为癌症化疗剂的潜在作用机制之一部分是由于膀胱癌细胞中Sp转录因子的表达降低。
Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. In this study, 10 – 25 µM curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of survivin, VEGF and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. The results show that curcumin induced proteasome-dependent downregulation of Sp1, Sp3 and Sp4 in 253JB-V and KU7 cells. Moreover, using RNA interference with small inhibitory RNAs for Sp1, Sp3 and Sp4, we observed that curcumin-dependent inhibition of nuclear factor κB (NFκB)-dependent genes such as bcl-2, survivin and cyclin D1, was also due, in part, to loss of Sp proteins. Curcumin also decreased bladder tumor growth in athymic nude mice bearing KU7 cells as xenografts and this was accompanied by decreased Sp1, Sp3 and Sp4 protein levels in tumors. These results demonstrate for the first time that one of the underlying mechanisms of action of curcumin as a cancer chemotherapeutic agent is due, in part, to decreased expression of Sp transcription factors in bladder cancer cells.