Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization.
Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization.
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DOI：
10.1371/journal.pone.0097847
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Salerno M
中科院分区：
文献类型：
--
作者：
De Robertis A;Mennillo F;Rossi M;Valensin S;Tunici P;Mori E;Caradonna N;Varrone M;Salerno M
肉瘤是表现出高分子异质性的间叶性肿瘤，在组织学水平上反映为存在50多种不同的亚型。遗传学和表观遗传学证据将Wnt信号的异常激活与人类肉瘤的生长和进展联系起来。这种现象主要通过自分泌环活性实现，通过基因扩增、Wnt配体和共受体的过表达或内源性Wnt拮抗剂的表观遗传沉默来维持。我们以前表明，药理学抑制Wnt信号介导的轴蛋白稳定在胶质母细胞瘤肿瘤中产生体外和体内抗肿瘤活性。在这里，我们报告说，靶向不同的肉瘤细胞系与Wnt抑制剂/轴蛋白稳定剂SEN 461产生较少的转化表型，支持的锚定非依赖性生长在体外的调制。在分子水平上，SEN 461处理增强了支架蛋白Axin 1的稳定性，Axin 1是具有肿瘤抑制功能的Wnt信号传导的关键负调节因子，导致与经典Wnt信号传导抑制一致的下游效应。小分子Axin稳定的遗传表型，通过Axin 1过表达，一致地导致软琼脂生长的强烈损害。重要的是，在雌性CD-1裸鼠体内异种移植模型中也观察到通过药理学Axin稳定的肉瘤生长抑制。我们的研究结果表明，具有Axin稳定活性的Wnt抑制剂作为某些类型肉瘤的潜在临床相关策略是有用的。
Sarcomas are mesenchymal tumors showing high molecular heterogeneity, reflected at the histological level by the existence of more than fifty different subtypes. Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas. This phenomenon, mainly accomplished by autocrine loop activity, is sustained by gene amplification, over-expression of Wnt ligands and co-receptors or epigenetic silencing of endogenous Wnt antagonists. We previously showed that pharmacological inhibition of Wnt signaling mediated by Axin stabilization produced in vitro and in vivo antitumor activity in glioblastoma tumors. Here, we report that targeting different sarcoma cell lines with the Wnt inhibitor/Axin stabilizer SEN461 produces a less transformed phenotype, as supported by modulation of anchorage-independent growth in vitro. At the molecular level, SEN461 treatment enhanced the stability of the scaffold protein Axin1, a key negative regulator of the Wnt signaling with tumor suppressor function, resulting in downstream effects coherent with inhibition of canonical Wnt signaling. Genetic phenocopy of small molecule Axin stabilization, through Axin1 over-expression, coherently resulted in strong impairment of soft-agar growth. Importantly, sarcoma growth inhibition through pharmacological Axin stabilization was also observed in a xenograft model in vivo in female CD-1 nude mice. Our findings suggest the usefulness of Wnt inhibitors with Axin stabilization activity as a potentialyl clinical relevant strategy for certain types of sarcomas.
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DOI：
10.1111/j.1349-7006.1999.tb00734.x
发表时间：
1999-03
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Iwao K;Miyoshi Y;Nawa G;Yoshikawa H;Ochi T;Nakamura Y
通讯作者：
Nakamura Y
影响因子：
3.7
作者：
James RG;Davidson KC;Bosch KA;Biechele TL;Robin NC;Taylor RJ;Major MB;Camp ND;Fowler K;Martins TJ;Moon RT
通讯作者：
Moon RT
影响因子：
3.4
作者：
Leow, Pay-Chin;Tian, Quan;Ee, Pui-Lai Rachel
通讯作者：
Ee, Pui-Lai Rachel
影响因子：
9.8
作者：
Bishop, E T;Bell, G T;Wheatley, D N
通讯作者：
Wheatley, D N
影响因子：
5.7
作者：
De Robertis, Alessandra;Valensin, Silvia;Salerno, Massimiliano
通讯作者：
Salerno, Massimiliano