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首页> 美国卫生研究院文献>British Journal of Cancer >Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17
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Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17

机译：低氧诱导的碳酸酐酶IX的胞外域脱落是一种金属蛋白酶依赖性过程受TACE / ADAM17调控

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摘要

Carbonic anhydrase IX (CA IX) is a transmembrane protein whose expression is strongly induced by hypoxia in a broad spectrum of human tumours. It is a highly active enzyme functionally involved in both pH control and cell adhesion. Its presence in tumours usually indicates poor prognosis. Ectodomain of CA IX is detectable in the culture medium and body fluids of cancer patients, but the mechanism of its shedding has not been thoroughly investigated. Here, we analysed several cell lines with natural and ectopic expression of CA IX to show that its ectodomain release is sensitive to metalloprotease inhibitor batimastat (BB-94) and that hypoxia maintains the normal rate of basal shedding, thus leading to concomitant increase in cell-associated and extracellular CA IX levels. Using CHO-M2 cells defective in shedding, we demonstrated that the basal CA IX ectodomain release does not require a functional TNFα-converting enzyme (TACE/ADAM17), whereas the activation of CA IX shedding by both phorbol-12-myristate-13-acetate and pervanadate is TACE-dependent. Our results suggest that the cleavage of CA IX ectodomain is a regulated process that responds to physiological factors and signal transduction stimuli and may therefore contribute to adaptive changes in the protein composition of tumour cells and their microenvironment.
机译：碳酸酐酶IX（CA IX）是一种跨膜蛋白，在广泛的人类肿瘤中，低氧强烈诱导其表达。它是一种高活性酶，功能上涉及pH值控制和细胞粘附。其在肿瘤中的存在通常预示不良预后。在癌症患者的培养基和体液中可检测到CA IX的Ectodomain，但其脱落机理尚未得到充分研究。在这里，我们分析了几种具有自然和异位表达CA IX的细胞系，以表明其胞外域释放对金属蛋白酶抑制剂batimastat（BB-94）敏感，缺氧维持了正常的基础脱落率，从而导致细胞的同时增加-相关和细胞外CA IX水平。使用脱落有缺陷的CHO-M2细胞，我们证明了基础CA IX胞外域释放不需要功能性TNFα转换酶（TACE / ADAM17），而phorbol-12-肉豆蔻酸酯13-激活CA IX脱落乙酸和过钒酸盐是TACE依赖的。我们的结果表明，CA IX胞外域的切割是一个受调节的过程，可响应生理因素和信号转导刺激，因此可能有助于肿瘤细胞及其微环境蛋白质组成的适应性变化。

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