Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins
Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins
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DOI：
10.1073/pnas.1703151114
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发表时间：
2017-07-11
影响因子：
11.1
通讯作者：
El-Sayed, Mostafa A.
中科院分区：
文献类型：
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作者：
Ali, Moustafa R. K.;Wu, Yue;El-Sayed, Mostafa A.
转移是大多数癌症相关死亡的原因，但目前的临床治疗无效。最近，金纳米颗粒（AuNPs）被发现可以抑制癌细胞迁移和防止转移。合理设计的金纳米粒子可以极大地提高其抗迁移性能，但其分子机制还需要探索。细胞骨架是与细胞迁移密切相关的细胞结构蛋白，表面受体整合素在控制细胞骨架的组织中起着关键作用。在此，我们开发了一种策略，通过靶向整合素，使用Arg-Gly-Asp（RGD）肽功能化的金纳米棒来抑制癌细胞迁移。为了增强效果，用808 nm近红外（NIR）光进一步激活AuNR，以产生用于光热治疗（PPTT）的热量，其中调节温度以不影响细胞活力/增殖。我们的研究结果证明了细胞形态的变化，观察到细胞骨架的变化，即，治疗后板状伪足和丝状伪足减少。Western blot分析表明整合素下游效应子被吸引向抗迁移方向。蛋白质组学结果表明，在四个信号通路，Rho GTP酶，肌动蛋白，微管和激酶相关的途径，这是整合素的下游调节剂的广泛扰动。由于整合素在控制细胞骨架、粘着斑、肌动球蛋白收缩以及肌动蛋白和微管组装中的主导作用，已经通过靶向整合素而被破坏。PPTT进一步增强了细胞骨架蛋白的重塑，并减少了迁移。总之，将AuNR靶向癌细胞整联蛋白的能力和PPTT的引入刺激了对细胞骨架的广泛调节，这为控制癌症转移的潜在医学应用提供了证据。
Metastasis is responsible for most cancer-related deaths, but the current clinical treatments are not effective. Recently, gold nanoparticles (AuNPs) were discovered to inhibit cancer cell migration and prevent metastasis. Rationally designed AuNPs could greatly benefit their anti-migration property, but the molecular mechanisms need to be explored. Cytoskeletons are cell structural proteins that closely relate to migration, and surface receptor integrins play critical roles in controlling the organization of cytoskeletons. Herein, we developed a strategy to inhibit cancer cell migration by targeting integrins, using Arg-Gly-Asp (RGD) peptide-functionalized gold nanorods. To enhance the effect, AuNRs were further activated with 808-nm near-infrared (NIR) light to generate heat for photothermal therapy (PPTT), where the temperature was adjusted not to affect the cell viability/proliferation. Our results demonstrate changes in cell morphology, observed as cytoskeleton protrusions-i.e., lamellipodia and filopodia-were reduced after treatment. The Western blot analysis indicates the downstream effectors of integrin were attracted toward the antimigration direction. Proteomics results indicated broad perturbations in four signaling pathways, Rho GTPases, actin, microtubule, and kinases-related pathways, which are the downstream regulators of integrins. Due to the dominant role of integrins in controlling cytoskeleton, focal adhesion, actomyosin contraction, and actin and microtubule assembly have been disrupted by targeting integrins. PPTT further enhanced the remodeling of cytoskeletal proteins and decreased migration. In summary, the ability of targeting AuNRs to cancer cell integrins and the introduction of PPTT stimulated broad regulation on the cytoskeleton, which provides the evidence for a potential medical application for controlling cancer metastasis.