BACKGROUND:Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. METHODS:The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression. RESULTS:BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. CONCLUSIONS:These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.

译文

背景:桦木酸(BA)抑制几种癌细胞系和肿瘤的生长,BA的作用归因于其线粒体毒性和多种促癌因子的抑制作用。先前的研究表明,BA可以诱导前列腺癌细胞中蛋白酶体依赖的特异性蛋白(Sp)转录因子Sp1,Sp3和Sp4降解,而这项研究的重点是BA在结肠癌细胞中的作用机理。
方法:采用标准化方法测定BA对体内结肠癌细胞增殖,凋亡和肿瘤生长的影响。通过蛋白质印迹分析BA对Sp蛋白和Sp调控基因产物的影响,并使用实时荧光定量PCR测定microRNA-27a(miR-27a)和ZBTB10 mRNA的表达。
结果:BA抑制RKO和SW480结肠癌细胞的生长并诱导其凋亡,并抑制携带RKO细胞作为异种移植物的无胸腺裸鼠的肿瘤生长。 BA还降低了在结肠癌细胞中过表达的Sp1,Sp3和Sp4转录因子的表达,并降低了几个Sp调节基因的水平,包括Survivin,血管内皮生长因子,NFκB的p65亚基,表皮生长因子受体,细胞周期蛋白D1和垂体肿瘤转化基因-1。 BA的作用机制取决于细胞的情况,因为BA分别在SW480和RKO细胞中分别诱导了蛋白酶体依赖性和蛋白酶体依赖性Sp1,Sp3和Sp4的下调。在RKO细胞中,BA诱导Sp1,Sp3和Sp4抑制的机制是由于活性氧(ROS)的诱导,ROS介导的microRNA-27a的抑制以及Sp阻遏物基因ZBTB10的诱导。
结论:这些结果表明BA在结肠癌细胞中的抗癌活性部分归因于Sp1,Sp3和Sp4转录因子的下调。但是,此响应的机制取决于单元上下文。

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