CD44 is a transmembrane cell adhesion molecule that is cleaved by the membrane proteinase, a disintegrin and metalloproteinase 10 (ADAM10), on the cell surface via ectodomain shedding after cholesterol depletion. Lipid raft-mediated CD44 shedding is essential for cancer cell invasion. As cell–cell and cell–matrix adhesions are critical for cancer progression, lipid raft-targeting agents may be effective for cancer therapy. Here, we found that curcumin and its derivatives induced the ADAM10-mediated shedding of CD44 in tumor cells. We also found that curcumin and the derivatives are membrane-active compounds whose effect depends on its planar backbone and the spatial arrangement of methoxy groups substituted on the two aromatic rings using giant unilamellar and plasma membrane vesicles. Curcumin and its derivatives with rigid backbones and hydroxy groups exerted membrane-domain-modulating activity, which may account for their pleiotropic effects via multiple signaling pathways involving membrane receptors. This study provides a basis for the use of membrane-active compounds, such as curcuminoids, to elucidate the roles of lipid rafts in cellular signaling, regulation of membrane-bound ADAM metalloproteinases, and the development of novel membrane lipid-based therapies.

中文翻译：

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姜黄素通过相分离调节膜筏完整性并诱导肿瘤细胞中 CD44 脱落

CD44 是一种跨膜细胞粘附分子，在胆固醇耗尽后通过胞外域脱落在细胞表面被膜蛋白酶（一种解整合素和金属蛋白酶 10 (ADAM10)）裂解。脂筏介导的 CD44 脱落对于癌细胞侵袭至关重要。由于细胞与细胞和细胞与基质的粘附对于癌症进展至关重要，因此脂筏靶向剂可能对癌症治疗有效。在这里，我们发现姜黄素及其衍生物诱导肿瘤细胞中 ADAM10 介导的 CD44 脱落。我们还发现姜黄素及其衍生物是膜活性化合物，其作用取决于其平面主链和使用巨型单层和质膜囊泡在两个芳香环上取代的甲氧基的空间排列。姜黄素及其具有刚性主链和羟基的衍生物发挥膜结构域调节活性，这可能解释了它们通过涉及膜受体的多种信号传导途径的多效性作用。这项研究为使用膜活性化合物（例如类姜黄素）阐明脂筏在细胞信号传导、膜结合 ADAM 金属蛋白酶的调节以及新型膜脂疗法的开发中的作用奠定了基础。