Hypoxia enhances cancer cell invasion through relocalization of the proprotein convertase furin from the trans-golgi network to the cell surface
Hypoxia enhances cancer cell invasion through relocalization of the proprotein convertase furin from the trans-golgi network to the cell surface
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DOI：
10.1002/jcp.22792
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发表时间：
2012-02-01
影响因子：
5.6
通讯作者：
Dubois, Claire M.
中科院分区：
文献类型：
--
作者：
Arsenault, Dominique;Lucien, Fabrice;Dubois, Claire M.
肿瘤缺氧与恶性进展密切相关，例如细胞侵袭和转移增加。尽管受缺氧影响的侵袭相关基因已得到很好的描述，但与缺氧反应相关的转录后机制（例如蛋白质运输和前蛋白加工）的贡献仍然知之甚少。前蛋白转化酶弗林蛋白酶是分泌途径的主要加工酶，存在于反高尔基体网络中，大多数研究支持这样的模型：内源性底物在该区室中被弗林蛋白酶加工。在这里，我们报告说，缺氧触发了弗林蛋白酶从跨高尔基体网络到癌细胞内体区室和细胞表面的意外重新定位。将这些细胞暴露在含氧量正常的条件下会逆转弗林蛋白酶的重新分布，这表明肿瘤微环境以高度调控的方式调节弗林蛋白酶的运输。对相关机制的评估表明，Rab4GTPase 依赖性回收以及弗林蛋白酶与细胞骨架锚定蛋白细丝蛋白 A 的相互作用对于弗林蛋白酶的细胞表面重新定位至关重要。干扰弗林蛋白酶与细丝蛋白-A 的结合，可以阻止弗林蛋白酶在细胞表面的重新定位，并消除癌细胞响应缺氧而迁移的能力。我们的观察结果支持这样的观点，即缺氧促进了外周加工室的形成，其中弗林蛋白酶易位以增强参与肿瘤发生的前蛋白的加工。 J.细胞。生理学。 227：789800，2012。(C)2011 Wiley 期刊公司。
Tumor hypoxia is strongly associated with malignant progression such as increased cell invasion and metastasis. Although the invasion-related genes affected by hypoxia have been well described, the contribution of post-transcriptional mechanisms such as protein trafficking and proprotein processing associated with the hypoxic response remains poorly understood. The proprotein convertase furin, the major processing enzyme of the secretory pathway, resides in the trans-Golgi network and most studies support a model where endogenous substrates are processed by furin within this compartment. Here, we report that hypoxia triggered an unexpected relocalization of furin from the trans-Golgi network to endosomomal compartments and the cell surface in cancer cells. Exposing these cells back to normoxic conditions reversed furin redistribution, suggesting that the tumor microenvironment modulates furin trafficking in a highly regulated manner. Assessment of the mechanisms involved revealed that both Rab4GTPase-dependent recycling and interaction of furin with the cytoskeletal anchoring protein, filamin-A, are essential for the cell surface relocalization of furin. Interference with the association of furin with filamin-A, prevented cell surface relocalization of furin and abolished the ability of cancer cells to migrate in response to hypoxia. Our observations support the notion that hypoxia promotes the formation of a peripheral processing compartment where furin translocates for enhanced processing of proproteins involved in tumorigenesis. J. Cell. Physiol. 227: 789800, 2012. (C) 2011 Wiley Periodicals, Inc.