Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway
Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway
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DOI：
10.1007/s10549-012-1986-8
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发表时间：
2012-08-01
影响因子：
3.8
通讯作者：
Ho, Yuan-Soon
中科院分区：
文献类型：
--
作者：
Chen, Li-Ching;Tu, Shih-Hsin;Ho, Yuan-Soon
细胞外基质（ECM）在乳腺肿瘤的发生、发展和侵袭中起着重要作用。赖氨酰氧化酶（LOX）是一种细胞外基质重塑酶，似乎在促进癌细胞运动和侵袭方面发挥作用。为了确定来自亚洲患者的乳腺肿瘤组织中LOX过表达是否与乳腺癌患者的无转移和总存活率的降低相关，使用实时RT-PCR分析在配对的肿瘤/正常组织样品中检查LOX的mRNA水平（n = 246个配对样品）。为了测试通过抑制LOX的活性（使用β-氨基丙腈（β-APN），LOX抑制剂）、mRNA表达（使用siRNA）或蛋白质表达（使用25 μ M厚朴酚）特异性靶向LOX是否减弱MDA-MB-231乳腺癌细胞的侵袭，进行癌细胞迁移测定。有趣的是，只有78.5%（n = 193）的乳腺癌肿瘤显示出可检测的LOX表达。近60%（n = 120）的病例属于第1组（肿瘤>正常，T > N）;在该组中，肿瘤细胞中的平均LOX表达是正常细胞的20.2倍。然而，在第2组（正常>肿瘤，N > T）中，所检查的大多数正常组织（80%，59/73）中的LOX表达水平比肿瘤组织中的LOX表达水平高不到5倍。侵袭性乳腺癌细胞系MDA-MB-231中活性LOX水平的增加伴随着粘着斑激酶在Tyr-576和桩蛋白在Tyr-118的磷酸化增加。我们还发现，加入β-APN（300 μ M）和厚朴酚（25 μ M），协同抑制MDA-MB-231细胞的迁移和侵袭。在这篇文章中，我们描述，第一次，高表达的LOX蛋白在乳腺肿瘤与正常组织相比，从亚洲患者。此外，结果表明，使用厚朴酚抑制LOX可能代表比使用β-APN更理想的乳腺癌治疗策略。
The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (beta-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 mu M magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor > normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal > tumor, N > T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of beta-APN (300 mu M) and magnolol (25 mu M), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of beta-APN.