The dietary terpene lupeol targets colorectal cancer cells with constitutively active Wnt/β-catenin signaling.
The dietary terpene lupeol targets colorectal cancer cells with constitutively active Wnt/β-catenin signaling.
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DOI：
10.1002/mnfr.201300155
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发表时间：
2013-11
影响因子：
5.2
通讯作者：
Mukhtar, Hasan
中科院分区：
文献类型：
--
作者：
Tarapore, Rohinton S.;Siddiqui, Imtiaz A.;Adhami, Vaqar M.;Spiegelman, Vladimir S.;Mukhtar, Hasan
无翅型小鼠乳腺肿瘤病毒整合位点家族（Wnt）/β-连环蛋白信号通路的异常激活是最常见的修饰，通常被认为是结直肠癌（CRC）的标志。通常在该途径中，β-连环蛋白从细胞质易位到细胞核，在细胞核中其充当支持肿瘤形成和进展的若干基因的转录调节剂。因此，任何能够减弱β-连环蛋白易位的药物对于CRC，特别是表现出组成型活性Wnt/β-连环蛋白信号传导的肿瘤都是非常有价值的。使用表现出Wnt/β-连环蛋白信号传导的差异表达的人CRC细胞，我们证明了用膳食三萜羽扇豆醇处理CRC细胞导致剂量依赖性i）细胞活力降低，ii）细胞凋亡诱导，iii）结肠生成潜力降低，iv）β-连环蛋白转录活性降低，和v）Wnt靶基因表达降低。最重要的是，观察到羽扇豆醇抑制β-连环蛋白从细胞质易位到细胞核。重要的是，羽扇豆醇的所有这些作用仅限于具有组成型活性Wnt/β-连环蛋白信号传导的细胞，而在缺乏组成型活性Wnt/β-连环蛋白信号传导的细胞中观察到可忽略的作用。此外，我们还证明了在具有组成性活性Wnt/β-连环蛋白的细胞中抑制Wnt信号传导导致羽扇豆醇功效的丧失，同时诱导Wnt信号传导使细胞对羽扇豆醇的抑制作用敏感。总之，我们的数据强烈支持羽扇豆醇对表现出组成型活性Wnt/β-连环蛋白信号传导的CRC细胞的功效。
Aberrant activation of the Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin signaling pathway is the most common modification, and often considered, a hallmark of colorectal cancer (CRC). Typically in this pathway the β-catenin translocates from the cytoplasm to the nucleus, where it functions as a transcription regulator of several genes that support tumor formation and progression. Thus, any agent that could attenuate the translocation of β-catenin could be extremely valuable against CRC, especially the tumors that exhibit constitutively active Wnt/β-catenin signaling. Using human CRC cells that exhibit differential expression of Wnt/β-catenin signaling, we demonstrate that treatment of CRC cells with dietary triterpene lupeol results in a dose dependent i) decrease in cell viability, ii) induction of apoptosis, iii) decrease in colonogenic potential, iv) decrease in β-catenin transcriptional activity, and v) decrease in the expression of Wnt target genes. Most importantly lupeol was observed to inhibit the translocation of β-catenin from the cytoplasm to the nucleus. Importantly, all these effects of lupeol were restricted to cells that harbor constitutively active Wnt/β-catenin signaling while negligible effects were observed in cells that lack constitutively active Wnt/β-catenin signaling. Further, we also demonstrate that inhibition of Wnt signaling in cells with constitutive active Wnt/β-catenin results in loss of lupeol efficacy while inducing Wnt signaling sensitizes the cells to inhibitory effects of lupeol. In summary, our data strongly advocate the efficacy of lupeol against CRC cells that exhibit constitutively active Wnt/β-catenin signaling.
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影响因子：
3.7
作者：
Chandra SH;Wacker I;Appelt UK;Behrens J;Schneikert J
通讯作者：
Schneikert J
影响因子：
8
作者：
Kim, TH;Xiong, H;Ren, B
通讯作者：
Ren, B
影响因子：
14.8
作者：
Chen, Baozhi;Dodge, Michael E.;Tang, Wei;Lu, Jianming;Ma, Zhiqiang;Fan, Chih-Wei;Wei, Shuguang;Hao, Wayne;Kilgore, Jessica;Williams, Noelle S.;Roth, Michael G.;Amatruda, James F.;Chen, Chuo;Lum, Lawrence
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Lum, Lawrence
影响因子：
3.3
作者：
Lima, Leonardo Mandalho;Perazzo, Fabio Ferreira;Bastos, Jairo Kenupp
通讯作者：
Bastos, Jairo Kenupp
影响因子：
3.3
作者：
Fernández, MA;de las Heras, B;Villar, A
通讯作者：
Villar, A