Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs.
Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs.
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DOI：
10.1186/1471-2407-12-564
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发表时间：
2012-11-30
期刊：
影响因子：
3.8
通讯作者：
Safe S
中科院分区：
文献类型：
--
作者：
Gandhy SU;Kim K;Larsen L;Rosengren RJ;Safe S
姜黄素可抑制多种癌细胞的生长，本实验室在膀胱和胰腺癌细胞中的研究表明，姜黄素下调特异性蛋白(Sp)转录因子Sp1、Sp3和Sp4以及致癌基因Sp调节的基因的表达。在这项研究中，我们研究了姜黄素和几种合成的环己酮和哌啶类似物在结肠癌细胞中的抗癌活性。采用标准化方法检测姜黄素及其类似物对结肠癌细胞增殖和凋亡的影响。Western blotts分析Sp蛋白和Sp调控基因产物的变化，实时定量聚合酶链式反应(Real Time PCR)检测microRNA-27a(miR-27a)、miR-20a、miR-17-5p以及ZBTB10和ZBTB4的mRNA表达。姜黄素及其合成环己酮和哌啶类似物对结肠癌细胞生长抑制作用(24小时)的半数抑制浓度(IC_(50))从10μM(姜黄素)到0.7μM(最有效的合成哌啶类似物RL197)，与姜黄素一起作为模型药物。姜黄素和RL197抑制RKO和SW480结肠癌细胞的生长并诱导细胞凋亡，伴随着特异性蛋白转录因子Sp1、Sp3和Sp4的下调以及Sp调控的基因，包括表皮生长因子受体、肝细胞生长因子受体、Survivin、bcl2、细胞周期蛋白D1和核因子κB(p65和p50)。姜黄素和RL197还可诱导细胞内产生活性氧(ROS)，与抗氧化剂谷胱甘肽共同处理可显著减弱姜黄素和RL197诱导的生长抑制和Sp1、Sp3、Sp4和Sp调控基因的下调。姜黄素/RL197诱导抑制Sp转录因子的机制是ROS依赖的，这是由于诱导了Sp抑制因子ZBTB10和ZBTB4，并下调了调节这些抑制因子的microRNAs(MiR)-27a、miR-20a和miR-17-5p。这些结果发现了一种新的高效的姜黄素衍生物，并表明在姜黄素和RL197诱导ROS的细胞中，一个重要的作用机制涉及miR-ZBTB10/ZBTB4的扰动，导致这些抑制物的诱导下调Sp转录因子和Sp调节基因。
Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells. The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression. The IC50 (half-maximal) values for growth inhibition (24 hr) of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), survivin, bcl-2, cyclin D1 and NFκB (p65 and p50). Curcumin and RL197 also induced reactive oxygen species (ROS), and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR)-27a, miR-20a and miR-17-5p that regulate these repressors. These results identify a new and highly potent curcumin derivative and demonstrate that in cells where curcumin and RL197 induce ROS, an important underlying mechanism of action involves perturbation of miR-ZBTB10/ZBTB4, resulting in the induction of these repressors which downregulate Sp transcription factors and Sp-regulated genes.
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影响因子：
3.8
作者：
Chintharlapalli S;Papineni S;Lei P;Pathi S;Safe S
通讯作者：
Safe S
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：
8
作者：
Kim, K.;Chadalapaka, G.;Lee, S-O;Yamada, D.;Sastre-Garau, X.;Defossez, P-A;Park, Y-Y;Lee, J-S;Safe, S.
通讯作者：
Safe, S.
DOI：
10.1093/gerona/51a.1.b66
发表时间：
1996-01-01
影响因子：
5.1
作者：
Adrian, GS;Seto, E;Bowman, BH
通讯作者：
Bowman, BH
影响因子：
9.2
作者：
Gupta, Subash C.;Kim, Ji Hye;Prasad, Sahdeo;Aggarwal, Bharat B.
通讯作者：
Aggarwal, Bharat B.