Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors.
Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors.
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DOI：
10.1186/1471-2407-11-371
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发表时间：
2011-08-24
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：
Chintharlapalli S;Papineni S;Lei P;Pathi S;Safe S
桦木酸（Betulinic acid，BA）对多种肿瘤细胞株和肿瘤生长具有抑制作用，其作用机制主要是通过对多种原癌因子的抑制和细胞毒作用来实现的。以往的研究表明，BA诱导蛋白酶体依赖性降解特异性蛋白（Sp）转录因子Sp1，Sp3和Sp 4在前列腺癌细胞中，本研究集中在BA在结肠癌细胞中的作用机制。使用标准化测定法测定BA对结肠癌细胞增殖和凋亡以及体内肿瘤生长的影响。Western blot分析BA对Sp蛋白和Sp调控基因产物的影响，真实的时间PCR检测microRNA-27 a（miR-27 a）和ZBTB 10 mRNA表达。BA抑制RKO和SW 480结肠癌细胞的生长和诱导凋亡，并抑制裸鼠移植瘤的生长。BA还降低了结肠癌细胞中过表达的Sp1、Sp3和Sp 4转录因子的表达，并降低了几种SP调节基因的水平，包括Survivin、血管内皮生长因子、NFκB的p65亚单位、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的作用机制依赖于细胞环境，因为BA分别诱导SW 480和RKO细胞中Sp1、Sp3和Sp 4的蛋白酶体依赖性和蛋白酶体非依赖性下调。在RKO细胞中，BA诱导的Sp1、Sp3和Sp 4阻遏的机制是由于活性氧（ROS）的诱导、ROS介导的microRNA-27 a的阻遏以及Sp阻遏基因ZBTB 10的诱导。这些结果表明，BA在结肠癌细胞中的抗癌活性部分是由于下调Sp1，Sp3和Sp 4转录因子;然而，这种反应的机制是细胞环境依赖性的。
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. 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. 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. 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.
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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：
2.9
作者：
Dehelean, Cristina A.;Feflea, Stefana;Amiji, Mansoor
通讯作者：
Amiji, Mansoor
影响因子：
3.5
作者：
BORRESEN, AL;LOTHE, RA;KOLODNER, RD
通讯作者：
KOLODNER, RD
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