Laser Dynamics Lab (LDL), School of Chemistry and Biochemistry, Georgia Institute of Technology , Atlanta, Georgia 30332-0400, United States.
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University , Providence, Rhode Island 02912, United States.
ACS Nano. 2017 Apr 25;11(4):3716-3726. doi: 10.1021/acsnano.6b08345. Epub 2017 Mar 27.
Most cancer patients die from metastasis. Recent studies have shown that gold nanoparticles (AuNPs) can slow down the migration/invasion speed of cancer cells and suppress metastasis. Since nuclear stiffness of the cell largely decreases cell migration, our hypothesis is that targeting AuNPs to the cell nucleus region could enhance nuclear stiffness, and therefore inhibit cell migration and invasion. Our results showed that upon nuclear targeting of AuNPs, the ovarian cancer cell motilities decrease significantly, compared with nontargeted AuNPs. Furthermore, using atomic force microscopy, we observed an enhanced cell nuclear stiffness. In order to understand the mechanism of cancer cell migration/invasion inhibition, the exact locations of the targeted AuNPs were clearly imaged using a high-resolution three-dimensional imaging microscope, which showed that the AuNPs were trapped at the nuclear membrane. In addition, we observed a greatly increased expression level of lamin A/C protein, which is located in the inner nuclear membrane and functions as a structural component of the nuclear lamina to enhance nuclear stiffness. We propose that the AuNPs that are trapped at the nuclear membrane both (1) add to the mechanical stiffness of the nucleus and (2) stimulate the overexpression of lamin A/C located around the nuclear membrane, thus increasing nuclear stiffness and slowing cancer cell migration and invasion.
大多数癌症患者死于转移。最近的研究表明，金纳米粒子（AuNPs）可以减缓癌细胞的迁移/侵袭速度并抑制转移。由于细胞核的硬度大大降低了细胞的迁移能力，我们假设将 AuNPs 靶向到细胞核区域可以增强核硬度，从而抑制细胞迁移和侵袭。我们的结果表明，与非靶向 AuNPs 相比，AuNPs 靶向细胞核后，卵巢癌细胞的迁移能力显著下降。此外，我们通过原子力显微镜观察到细胞核硬度增强。为了了解抑制癌细胞迁移/侵袭的机制，我们使用高分辨率三维成像显微镜清楚地观察到靶向 AuNPs 的准确位置，结果表明 AuNPs 被捕获在核膜上。此外，我们观察到核纤层蛋白 A/C 蛋白的表达水平大大增加，该蛋白位于核膜内，作为核纤层的结构成分，增强核硬度。我们提出，被捕获在核膜上的 AuNPs 既（1）增加了核的力学硬度，又（2）刺激了核膜周围定位的核纤层蛋白 A/C 的过表达，从而增加了核硬度并减缓了癌细胞的迁移和侵袭。
