Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth.
Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth.
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DOI：
10.1016/j.yexcr.2010.04.027
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发表时间：
2010-08-01
影响因子：
3.7
通讯作者：
Safe S
中科院分区：
文献类型：
--
作者：
Jutooru I;Chadalapaka G;Sreevalsan S;Lei P;Barhoumi R;Burghardt R;Safe S
三氧化二砷在癌细胞中具有抗增殖、抗血管生成和促凋亡活性，并且与这些反应相关的许多基因受到特异性蛋白（Sp）转录因子的调控。用三氧化二砷治疗源自泌尿系统（膀胱和前列腺）和胃肠道（胰腺和结肠）肿瘤的癌细胞表明，这些细胞对该药剂的抗增殖作用表现出不同的反应性，这与它们对Sp1、Sp3和Sp4的不同抑制是平行的相同细胞系中的蛋白质。以三氧化二砷敏感的KU7和无反应的253JB-V膀胱癌细胞为模型，我们发现，在KU7细胞中，≤ 5 μ M的三氧化二砷降低了Sp1、Sp3和Sp4以及几种Sp-dependent基因和反应，包括细胞周期蛋白D1、表皮生长因子受体、bcl-2、生存素和血管内皮生长因子，而在高达15 μ M的浓度下，在253JB-V细胞中观察到最小的影响。三氧化二砷也抑制裸鼠KU7细胞移植瘤的生长，并显著降低了Sp1、Sp3和Sp4的表达。氧化应激抑制剂，如谷胱甘肽或二硫苏糖醇保护KU7细胞从三氧化二砷诱导的抗增殖活性和Sp抑制，而谷胱甘肽耗竭敏感253JB-V细胞三氧化二砷。机制研究表明，三氧化二砷依赖性下调Sp和Sp依赖性基因是由于线粒体膜电位降低和活性氧的诱导，过氧化物在介导这些反应中的作用得到证实，使用过氧化氢。
Arsenic trioxide exhibits antiproliferative, antiangiogenic and proapoptotic activity in cancer cells, and many genes associated with these responses are regulated by specificity protein (Sp) transcription factors. Treatment of cancer cells derived from urologic (bladder and prostate) and gastrointestinal (pancreas and colon) tumors with arsenic trioxide demonstrated that these cells exhibited differential responsiveness to the antiproliferative effects of this agent and this paralleled their differential repression of Sp1, Sp3 and Sp4 proteins in the same cell lines. Using arsenic trioxide responsive KU7 and non-responsive 253JB-V bladder cancer cells as models, we show that in KU7 cells, ≤ 5 μM arsenic trioxide decreased Sp1, Sp3 and Sp4 and several Sp-dependent genes and responses including cyclin D1, epidermal growth factor receptor, bcl-2, survivin and vascular endothelial growth factor, whereas at concentrations up to 15 μM, minimal effects were observed in 253JB-V cells. Arsenic trioxide also inhibited tumor growth in athymic mice bearing KU7 cells as xenografts, and expression of Sp1, Sp3 and Sp4 was significantly decreased. Inhibitors of oxidative stress such as glutathione or dithiothreitol protected KU7 cells from arsenic trioxide-induced antiproliferative activity and Sp repression, whereas glutathione depletion sensitized 253JB-V cells to arsenic trioxide. Mechanistic studies suggested that arsenic trioxide-dependent downregulation of Sp and Sp-dependent genes was due to decreased mitochondrial membrane potential and induction of reactive oxygen species, and the role of peroxides in mediating these responses was confirmed using hydrogen peroxide.
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影响因子：
6.4
作者：
Chintharlapalli, Sudhakar;Papineni, Sabitha;Abdelrahim, Maen;Abudayyeh, Ala;Jutooru, Indira;Chadalapaka, Gayathri;Wu, Fei;Mertens-Talcott, Susanne;Vanderlaag, Kathy;Cho, Sung Dae;Smith, Roger, III;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
11.2
作者：
Chadalapaka G;Jutooru I;Chintharlapalli S;Papineni S;Smith R 3rd;Li X;Safe S
通讯作者：
Safe S
影响因子：
4
作者：
Han, SS;Kim, K;Park, S
通讯作者：
Park, S
影响因子：
5.6
作者：
Kang, Young-Hee;Lee, Su-Jae
通讯作者：
Lee, Su-Jae
影响因子：
11.2
作者：
Chintharlapalli, Sudhakar;Papineni, Sabitha;Safe, Stephen
通讯作者：
Safe, Stephen