Invadopodia biogenesis is regulated by caveolin-mediated modulation of membrane cholesterol levels
Invadopodia biogenesis is regulated by caveolin-mediated modulation of membrane cholesterol levels
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DOI：
10.1111/j.1582-4934.2008.00568.x
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发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Buccione, Roberto
中科院分区：
文献类型：
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作者：
Caldieri, Giusi;Giacchetti, Giada;Buccione, Roberto
侵袭足细胞是侵袭性肿瘤细胞在细胞外基质(ECM)底物上生长时形成的具有蛋白质降解活性的突起。显然，侵袭足是专门的膜域，作为信号转导和极化传递的场所，是聚焦ECM降解所需的成分。出于这些原因，英多波迪亚是研究肿瘤细胞局部细胞外基质降解的模型。我们研究了内足虫膜结构域的特征，以及它们的组成改变如何影响内足动物的生物发生和功能。这是通过多种途径实现的，包括控制质膜上的胆固醇和其他脂类的水平，通过作用于小窝蛋白1的表达和磷酸化改变胆固醇的运输。我们的研究表明，胆固醇耗竭会损害内翻足的形成和持久性，内翻足本身就是富含胆固醇的细胞膜。此外，通过提供简单的胆固醇可以有效地逆转小凹蛋白1基因敲除后对内陷足形成和细胞外基质降解的抑制。此外，小窝蛋白3DGV表达的抑制效应也同样被胆固醇的供应逆转。我们认为，内翻足动物的生物发生、功能和结构完整性依赖于适当水平的质膜胆固醇，内翻足动物表现出富含胆固醇的膜的特性。此外，小窝蛋白1通过调节质膜上的胆固醇平衡来发挥其在内向足类形成中的作用。这些发现支持胆固醇、癌症和小窝蛋白1之间的联系，为胆固醇在癌症进展中的作用提供了进一步的理解，并为他汀类药物的抗癌活性提供了一个机制框架，这与他们的血液降胆固醇特性密切相关。
Invadopodia are proteolytically active protrusions formed by invasive tumoural cells when grown on an extracellular matrix (ECM) substratum. Clearly, invadopodia are specialized membrane domains acting as sites of signal transduction and polarized delivery of components required for focalized ECM degradation. For these reasons, invadopodia are a model to study focal ECM degradation by tumour cells. We investigated the features of invadopodia membrane domains and how altering their composition would affect invadopodia biogenesis and function. This was achieved through multiple approaches including manipulation of the levels of cholesterol and other lipids at the plasma membrane, alteration of cholesterol trafficking by acting on caveolin 1 expression and phosphorylation. We show that cholesterol depletion impairs invadopodia formation and persistence, and that invadopodia themselves are cholesterol-rich membranes. Furthermore, the inhibition of invadopodia formation and ECM degradation after caveolin 1 knock-down was efficiently reverted by simple provision of cholesterol. In addition, the inhibitory effect of caveolin 3DGV expression, a mutant known to block cholesterol transport to the plasma membrane, was similarly reverted by provision of cholesterol. We suggest that invadopodia biogenesis, function and structural integrity rely on appropriate levels of plasma membrane cholesterol, and that invadopodia display the properties of cholesterol-rich membranes. Also, caveolin 1 exerts its function in invadopodia formation by regulating cholesterol balance at the plasma membrane. These findings support the connection between cholesterol, cancer and caveolin 1, provide further understanding of the role of cholesterol in cancer progression and suggest a mechanistic framework for the proposed anti-cancer activity of statins, tightly related to their blood cholesterol-lowering properties.