Oroxylin A inhibits invasion and migration through suppressing ERK/GSK-3 signaling in snail-expressing non-small-cell lung cancer cells
Oroxylin A inhibits invasion and migration through suppressing ERK/GSK-3 signaling in snail-expressing non-small-cell lung cancer cells
复制标题
Oroxylin A 通过抑制表达 snail 的非小细胞肺癌细胞中的 ERK/GSK-3 信号传导来抑制侵袭和迁移
DOI：
10.1002/mc.22456
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发表时间：
2016-12-01
影响因子：
4.6
通讯作者：
Lu, Na
中科院分区：
文献类型：
--
作者：
Wei, Libin;Yao, Yuyuan;Lu, Na
Snail与肿瘤的侵袭、转移和复发密切相关，并指示癌症患者的预后。Snail的过表达增加了癌细胞的运动性和侵袭性，这已成为抗转移治疗的靶点。Oroxylin A是一种从紫藤中提取的天然化合物，有报道可抑制乳腺癌的侵袭和迁移。在这项研究中，我们研究了木脂素A对肺细胞的抗侵袭作用，并揭示了其潜在的机制。结果表明，在表达Snail的95-D和A549细胞中，oroxylin A可抑制迁移和侵袭，而对不表达Snail的GLC-82细胞影响不大。此外，在GLC-82细胞中转染Snail载体后增强的Snail表达被oroxylin A降低。Snail还可以诱导上皮-间质转化。我们发现，oroxylin A可以通过抑制Snail表达来逆转TGF 1诱导的上皮-间质转化。结果表明，oroxylin A上调E-cadherin的表达，下调vimentin、MMP-9和CD 44 v6的表达，从而抑制肿瘤的迁移和侵袭。在机制上，我们证明了木脂素A抑制ERK而不是AKT通路的活化，然后促进GSK-3的活化以减少Snail蛋白含量。最后，我们建立了A549细胞的移植、转移和原位模型，发现在体内，oroxylin A抑制A549细胞的生长和肺转移。综上所述，我们提出，木脂素A可能是一个有前途的候选人靶向肿瘤转移。(c)2016 Wiley Periodicals，Inc.
Snail is closely linked to tumor invasion, metastasis, and recurrence and indicates prognosis of patients suffering from cancer. Overexpression of Snail increases motility and invasiveness of cancer cells, which has become target for anti-metastatic treatment. Oroxylin A, a natural compound extracted from Scutellaria radix, has been reported to inhibit invasion and migration in breast cancer. In this study, we investigated the anti-invasive effect of oroxylin A on lung cells and uncovered its underlying mechanism. The results suggested that oroxylin A could inhibit migration and invasion in Snail-expressing 95-D, and A549 cells whereas it had little effect on non-expressing GLC-82 cells. Furthermore, enhanced Snail expression after transfection of Snail vector in GLC-82 cells is decreased by oroxylin A. Snail can also induce epithelial-mesenchymal transition. We found oroxylin A could reverse TGF1-induced epithelial-mesenchymal transition by inhibiting Snail expression. As a result, oroxylin A up-regulated E-cadherin expression and down-regulated vimentin, MMP-9, and CD44v6 expression, which could lead to the inhibition of tumor migration and invasion. Mechanically, we demonstrated that oroxylin A suppressed activation of ERK instead of AKT pathway and then promoted activation of GSK-3 to reduce Snail protein content. Finally, we established transplanted, metastatic, and orthotopic models of A549 cells, and found that oroxylin A inhibited the growth and lung metastasis of A549 cells in vivo. Taken together, we proposed that oroxylin A might be a promising candidate targeting tumor metastasis. (c) 2016 Wiley Periodicals, Inc.