Department of Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, I-20133 Milan, Italy.
Int J Oncol. 2011 Jul;39(1):225-34. doi: 10.3892/ijo.2011.1030. Epub 2011 May 3.
The proapoptotic activity of nuclear clusterin (nCLU) in cancer cells is now well established. We previously showed that nCLU decreases the motility of prostate cancer cells by triggering a dramatic dismantling of the actin cytoskeleton. Here, we sought to unravel the molecular mechanisms of the antimetastatic activity of nCLU. We found that nCLU: i) decreases LIMK1 expression, thus increasing the levels of the active (unphosphorylated) form of cofilin, the well known actin depolymerizing factor; ii) binds to vimentin, sequestering the protein from its adhesion sites at the cell periphery, thus interfering with its role in cell motility and adhesion; iii) affects the intracellular distribution of E-cadherin (the major component of epithelial adherens junctions) which appears to be diffusely distributed in the cells. Through these mechanisms nCLU reduces the migratory/invasive behavior of PC3 cells; this effect is further demonstrated by a decreased secretion of active MMP-2 from the cells. Thus, in addition to its proapoptotic function, nCLU also exerts a strong anti-migratory/anti-invasive activity in prostate cancer cells, by interfering with the cytoskeletal components and by decreasing MMP-2 activity.
核聚集蛋白（nCLU）在癌细胞中的促凋亡活性已得到充分证实。我们之前曾表明，nCLU 通过触发肌动蛋白细胞骨架的剧烈解体来降低前列腺癌细胞的迁移能力。在这里，我们试图揭示 nCLU 的抗转移活性的分子机制。我们发现 nCLU：i）降低 LIMK1 的表达，从而增加了肌动蛋白解聚因子（cofilin）的活性（未磷酸化）形式的水平；ii）与波形蛋白结合，将其从细胞边缘的粘附部位隔离出来，从而干扰其在细胞迁移和粘附中的作用；iii）影响 E-钙粘蛋白（上皮细胞黏附连接的主要成分）的细胞内分布，其似乎在细胞中弥散分布。通过这些机制，nCLU 降低了 PC3 细胞的迁移/侵袭行为；这一效应还通过细胞中活性 MMP-2 的分泌减少得到进一步证实。因此，除了其促凋亡功能外，nCLU 还通过干扰细胞骨架成分和降低 MMP-2 活性，在前列腺癌细胞中发挥强烈的抗迁移/抗侵袭活性。
