He Xia, Chen Xin, Li Bogang, Ji Jianxin, Chen Shuang
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
University of Chinese Academy of Sciences, Beijing, China.
FEBS Lett. 2017 Dec;591(23):3861-3871. doi: 10.1002/1873-3468.12895. Epub 2017 Nov 24.
Macrophages are abundant in the tumor microenvironment. They are highly plastic and able to acquire pro-tumoral phenotypes in response to microenvironmental stimuli. When we treated RAW 264.7 macrophages with inhibitors of various oncogenic pathways, we found that the focal adhesion kinase (FAK) inhibitors PF573228 and TAE226 could induce cell multinucleation by suppressing furrowing and cytokinesis. This failure in cytokinesis involves Rac1, whose activity is elevated by FAK inhibitors, and the p21-activated kinases, comprising the downstream effectors of Rac. We also investigated the influence of cell multinucleation on macrophage physiology in RAW 264.7 cells. This is the first study to report that FAK inhibitors suppress furrow ingression and early cytokinesis. Of note, we found that FAK inhibitors caused a dramatic increase in pro-tumoral cytokines in multinuclear cells, suggesting the potential to convert macrophages into pro-tumoral phenotypes.
巨噬细胞在肿瘤微环境中大量存在。它们具有高度可塑性，能够响应微环境刺激而获得促肿瘤表型。当我们用各种致癌途径的抑制剂处理RAW 264.7巨噬细胞时，我们发现粘着斑激酶（FAK）抑制剂PF573228和TAE226可通过抑制沟缢和胞质分裂诱导细胞多核化。这种胞质分裂失败涉及Rac1，其活性被FAK抑制剂提高，以及p21激活激酶，后者是Rac的下游效应器。我们还研究了细胞多核化对RAW 264.7细胞中巨噬细胞生理学的影响。这是第一项报道FAK抑制剂抑制沟缢侵入和早期胞质分裂的研究。值得注意的是，我们发现FAK抑制剂导致多核细胞中促肿瘤细胞因子急剧增加，这表明有可能将巨噬细胞转化为促肿瘤表型。
