Honokiol inhibits non-small cell lung cancer cell migration by targeting PGE₂-mediated activation of β-catenin signaling.
Honokiol inhibits non-small cell lung cancer cell migration by targeting PGE₂-mediated activation of β-catenin signaling.
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DOI：
10.1371/journal.pone.0060749
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Katiyar SK
中科院分区：
文献类型：
--
作者：
Singh T;Katiyar SK
肺癌由于其转移到远处器官而仍然是死亡的主要原因。我们研究了厚朴（Magnolia植物的生物活性成分）对人非小细胞肺癌（NSCLC）细胞迁移的影响及其分子机制。使用体外细胞迁移试验，我们发现用和诺昔康处理A549、H1299、H460和H226 NSCLC细胞以剂量依赖性方式抑制这些细胞的迁移，这与环氧化酶-2（考克斯-2）和前列腺素E2（PGE 2）水平的降低有关。塞来昔布，一种考克斯-2抑制剂，也抑制细胞迁移。和厚朴酚抑制PGE 2增强的NSCLC细胞迁移，抑制A549和H1299细胞中考克斯-2上游调节因子NF-κB/p65的活化，用NF-κB抑制剂咖啡酸苯乙酯处理细胞也抑制NSCLC细胞的迁移。PGE 2已被证明激活β-连环蛋白信号传导，这有助于癌细胞迁移。因此，我们检查了和诺啡肽对β-连环蛋白信号传导的影响。观察到用和厚朴酚处理NSCLC细胞降解胞浆β-catenin，减少β-catenin的核积聚，并下调基质金属蛋白酶（MMP）-2和MMP-9，其是β-catenin的下游靶点，并且在癌细胞转移中起关键作用。荣誉增强：（i）酪蛋白激酶-1 α、糖原合成酶激酶-3 β的水平，和（ii）关键残基Ser 45、Ser 33/37和Thr 41上β-连环蛋白的磷酸化。这些事件在β-catenin的降解或失活中起重要作用。塞来昔布治疗还减少了NSCLC细胞中β-连环蛋白的核积聚。Wnt/β-catenin通路抑制剂FH 535可抑制PGE 2诱导的A549和H1299细胞迁移。这些结果表明，和厚朴酚通过靶向PGE 2介导的β-catenin信号转导激活来抑制非小细胞肺癌细胞的迁移。
Lung cancer remains a leading cause of death due to its metastasis to distant organs. We have examined the effect of honokiol, a bioactive constituent from the Magnolia plant, on human non-small cell lung cancer (NSCLC) cell migration and the molecular mechanisms underlying this effect. Using an in vitro cell migration assay, we found that treatment of A549, H1299, H460 and H226 NSCLC cells with honokiol resulted in inhibition of migration of these cells in a dose-dependent manner, which was associated with a reduction in the levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). Celecoxib, a COX-2 inhibitor, also inhibited cell migration. Honokiol inhibited PGE2-enhanced migration of NSCLC cells, inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in A549 and H1299 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited migration of NSCLC cells. PGE2 has been shown to activate β-catenin signaling, which contributes to cancer cell migration. Therefore, we checked the effect of honokiol on β-catenin signaling. It was observed that treatment of NSCLC cells with honokiol degraded cytosolic β-catenin, reduced nuclear accumulation of β-catenin and down-regulated matrix metalloproteinase (MMP)-2 and MMP-9, which are the down-stream targets of β-catenin and play a crucial role in cancer cell metastasis. Honokiol enhanced: (i) the levels of casein kinase-1α, glycogen synthase kinase-3β, and (ii) phosphorylation of β-catenin on critical residues Ser45, Ser33/37 and Thr41. These events play important roles in degradation or inactivation of β-catenin. Treatment of celecoxib also reduced nuclear accumulation of β-catenin in NSCLC cells. FH535, an inhibitor of Wnt/β-catenin pathway, inhibited PGE2-enhanced cell migration of A549 and H1299 cells. These results indicate that honokiol inhibits non-small cell lung cancer cells migration by targeting PGE2-mediated activation of β-catenin signaling.
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