Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration
Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration
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DOI：
10.1007/s13277-015-3341-2
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发表时间：
2015-08-01
期刊：
影响因子：
--
通讯作者：
Jiang, Yangfu
中科院分区：
文献类型：
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作者：
Cui, Anguo;Hua, Hui;Jiang, Yangfu
黄曲霉毒素B1（AFB 1）是一种强致癌物质。流行病学研究表明，AFB 1暴露与人类肺癌之间存在关联。黄曲霉毒素B1可通过其代谢产物黄曲霉毒素B1 - 8，9-外环氧化物（AFB 1 - 8，9-exo-epoxide）作为诱变剂与DNA发生作用，从而诱导抑癌基因p53等基因突变。此外，最近的研究表明，AFB 1正调节I型胰岛素样生长因子受体（IGF-IR）信号在肝癌细胞。本研究旨在探讨黄曲霉毒素B1对肺癌细胞Src激酶和胰岛素受体底物（IRS）的影响，以及黄曲霉毒素B1对肺癌细胞迁移的影响。为此，AFB 1对IRS表达，Src，Akt和ERK磷酸化的影响通过Western印迹分析来测量。伤口愈合实验检测肺癌细胞的迁移能力。AFB 1下调IRS 1但上调IRS 2，通过正向调节IRS 2的稳定性和IRS 1在肺癌细胞系A549和SPCA-1中的蛋白酶体降解。此外，AFB 1诱导Src、Akt和ERK 1/2磷酸化。用Src抑制剂saracatinib处理肺癌细胞可以消除AFB 1诱导的IRS 2积累。此外，AFB 1刺激肺癌细胞迁移，这可以被saracatinib抑制。我们的结论是，黄曲霉毒素B1可能上调IRS 2和刺激肺癌细胞迁移通过Src。
AflatoxinB1 (AFB1) is well known as a potent carcinogen. Epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. AFB1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB1-8,9-exo-epoxide, which acts as a mutagen to react with DNA. In addition, recent study demonstrates AFB1 positively regulates type I insulin-like growth factor receptor (IGF-IR) signaling in hepatoma cells. The current study aims to determine the effects of AFB1 on Src kinase and insulin receptor substrate (IRS) in lung cancer cells and the effects of AFB1 on lung cancer cell migration. To this end, the effects of AFB1 on IRS expression, Src, Akt, and ERK phosphorylation were measured by Western blot analysis. The migration of lung cancer cells was detected by wound-healing assay. AFB1 downregulates IRS1 but paradoxically upregulates IRS2 through positive regulation of the stability of IRS2 and the proteasomal degradation of IRS1 in lung cancer cell lines A549 and SPCA-1. In addition, AFB1 induces Src, Akt, and ERK1/2 phosphorylation. Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB1-induced IRS2 accumulation. Moreover, AFB1 stimulates lung cancer cell migration, which can be inhibited by saracatinib. We conclude that AFB1 may upregulate IRS2 and stimulate lung cancer cell migration through Src.