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首页> 外文期刊>British Journal of Cancer >Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells
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Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

机译：将IGF系统和HIF-1共同靶向抑制（三阴性）乳腺癌细胞的迁移和侵袭

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Background: Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways.Methods: Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR.Results: IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration.Conclusions: IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies.
机译：背景：由于缺乏合适的药物靶标，转移性三阴性乳腺癌大多无法治愈。胰岛素样生长因子（IGF）系统可以提供这样的靶标，而IGF-1受体（IGF-1R）导向的药物已经可用，但似乎无法控制系统的所有复杂性，包括与低氧-方法：通过刮擦伤口愈合和Boyden室评估三阴性MDA-231乳腺癌细胞的迁移及其对IGFs，IGF-1R抑制剂NVP-AEW541和IGF-2隔离单克隆抗体MAB292的调节作用。分析;还评估了拓扑替康（抑制缺氧诱导因子-1（HIF-1））在缺氧条件下的作用。通过蛋白质印迹和qPCR评估了IGF和HIF-1途径的组成成分和药物调节水平。结果：IGF-1R抑制剂NVP-AEW541不能消除IGF诱导的MDA-231细胞迁移，而MAB292隔离IGF-2则明显减少了细胞迁移。在缺氧条件下，拓扑替康也可能有效，可能是通过降低HIF-1诱导的IGF-2释放。同时靶向IGF-1R和IGF-2或HIF-1完全消除了细胞迁移。结论：IR激活可能是NVP-AEW541无法抑制MDA-231细胞迁移的原因。靶向配体的化合物或IGF和HIF-1系统的共抑制作用可能会阻止代偿信号的激活，从而为基于IGF-1R抑制剂的治疗提供了有价值的补充。

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