The tumor suppressor activity of the lysyl oxidase propeptide reverses the invasive phenotype of Her-2/neu-driven breast cancer
The tumor suppressor activity of the lysyl oxidase propeptide reverses the invasive phenotype of Her-2/neu-driven breast cancer
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DOI：
10.1158/0008-5472.can-06-3867
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Sonenshein, Gail E.
中科院分区：
文献类型：
--
作者：
Min, Chengyin;Kirsch, Kathrin H.;Sonenshein, Gail E.
在NIH 3T3成纤维细胞中发现赖氨酸氧化酶基因（LOX）的表达抑制ras癌基因的转化活性，因此被命名为ras精确基因（rrg）。赖氨酸氧化酶（Lysyl oxidase， LOX）是一种50 kda的无活性前酶（Pro-LOX），通过蛋白水解裂解生成32 kda的功能性酶和18 kda的前肽（LOX- pp）。最近，NIH 3T3细胞中LOX基因的ras精确活性被定位到其前肽区。在这里，我们首次证明LOX-PP抑制由Her-2/neu驱动的乳腺癌细胞的转化，Her-2/neu是Ras的上游激活剂。培养的Her-2/新驱动乳腺癌细胞中LOX-PP的表达抑制Akt、细胞外信号调节激酶和核因子κ B的激活。通过降低Snail和vimentin水平来判断，LOX-PP恢复了Her-2/ new诱导的上皮向间质转化；e -钙粘蛋白、γ -连环蛋白和雌激素受体α上调；以及在Matrigel中迁移或形成分支殖民地的能力下降。此外，LOX-PP在裸鼠异种移植模型中抑制Her-2/新肿瘤的形成。因此，LOX-PP抑制Her-2/neu诱导的信号级联反应，促进更具侵袭性的表型，可能为治疗Her-2/neu驱动的乳腺癌提供新的途径。
Expression of the lysyl oxidase gene (LOX) was found to inhibit the transforming activity of the ras oncogene in NIH 3T3 fibroblasts and was hence named the ras recision gene (rrg). Lysyl oxidase (LOX) is synthesized and secreted as a 50-kDa inactive proenzyme (Pro-LOX), which is processed by proteolytic cleavage to a functional 32-kDa enzyme and an 18-kDa propeptide (LOX-PP). Recently, the ras recision activity of the LOX gene in NIH 3T3 cells was mapped to its propeptide region. Here, we show for the first time that LOX-PP inhibits transformation of breast cancer cells driven by Her-2/neu, an upstream activator of Ras. LOX-PP expression in Her-2/ neu-driven breast cancer cells in culture suppressed Akt, extracellular signal-regulated kinase, and nuclear factor-kappa B activation. Her-2/neu-induced epithelial to mesenchymal transition was reverted by LOX-PP, as judged by reduced levels of Snail and vimentin; up-regulation of E-cadherin, gamma-catenin, and estrogen receptor alpha; and decreased ability to migrate or to form branching colonies in Matrigel. Furthermore, LOX-PP inhibited Her-2/neu tumor formation in a nude mouse xenograft model. Thus, LOX-PP inhibits signaling cascades induced by Her-2/neu that promote a more invasive phenotype and may provide a novel avenue for treatment of Her-2/neu-driven breast carcinomas.