Γ-Ionizing radiation-induced activation of the EGFR-p38/ERK-STAT3/CREB-1-EMT pathway promotes the migration/invasion of non-small cell lung cancer cells and is inhibited by podophyllotoxin acetate
Γ-Ionizing radiation-induced activation of the EGFR-p38/ERK-STAT3/CREB-1-EMT pathway promotes the migration/invasion of non-small cell lung cancer cells and is inhibited by podophyllotoxin acetate
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DOI：
10.1007/s13277-015-4548-y
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发表时间：
2016-06-01
期刊：
影响因子：
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通讯作者：
Park, Jong Kuk
中科院分区：
文献类型：
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作者：
Cho, Jeong Hyun;Hong, Wan Gi;Park, Jong Kuk
在这里，我们报道了一种新的细胞内信号通路，参与了伽玛电离辐射(IR)诱导的迁移/侵袭，并表明鬼臼毒素(PA)抑制了IR诱导的A549细胞(非小细胞肺癌细胞系)的侵袭和迁移。我们的结果显示IR增加了A549细胞的侵袭/迁移，而10 nM PA处理后这种作用被减弱。PA还可抑制基质金属蛋白(MMP2)、MMP9和波形蛋白的表达/活性，提示PA可阻断IR诱导的上皮-间充质转化(EMT)。IR诱导的侵袭/迁移增加与EGFR-AKT的激活有关，PA可抑制这一作用。P38和p44/42ERK也参与了IR诱导的侵袭/迁移，PA和每个MAPK的抑制剂联合治疗可协同阻断这种侵袭/迁移。在转录因子方面，IR诱导的cAMP反应元件结合蛋白-1(CREB-1)和信号转导和转录激活子3(STAT3)的增加增加了侵袭/迁移和EMT。PA还抑制这些转录因子，从而阻断IR诱导的侵袭/迁移。综上所述，这些结果表明，IR通过激活EGFR-p38/ERK-CREB-1/STAT3-EMT通路来诱导癌细胞的侵袭/迁移，而PA阻断这一途径以抑制IR诱导的侵袭/迁移。
Here, we report a new intracellular signaling pathway involved in gamma-ionizing radiation (IR)-induced migration/invasion and show that podophyllotoxin acetate (PA) inhibits the IR-induced invasion and migration of A549 cells (a non-small cell lung cancer (NSCLC) cell line). Our results revealed that IR increased the invasion/migration of A549 cells, and this effect was decreased by 10 nM PA treatment. PA also inhibited the expressions/activities of matrix metalloprotase (MMP) -2, MMP-9, and vimentin, suggesting that PA could block the IR-induced epithelial-mesenchymal transition (EMT). The IR-induced increases in invasion/migration were associated with the activation of EGFR-AKT, and PA inhibited this effect. P38 and p44/42 ERK were also involved in IR-induced invasion/migration, and combined treatments with PA plus inhibitors of each MAPK synergistically blocked this invasion/migration. In terms of transcription factors (TFs), IR-induced increases in cyclic AMP response element-binding protein-1 (CREB-1) and signal transducer and activator of transcription 3 (STAT3) increased invasion/migration and EMT. PA also inhibited these transcription factors and then blocked IR-induced invasion/migration. Collectively, these results indicate that IR induces cancer cell invasion/migration by activating the EGFR-p38/ERK-CREB-1/STAT3-EMT pathway and that PA blocks this pathway to inhibit IR-induced invasion/migration.