Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins

Abstract

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 antimigration 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.gold nanorods | cytoskeleton | integrin | metastasis | plasmonic photothermal therapy

Biological responses to nanomaterials: understanding nano-bio effects on cell behaviors

“…Furthermore, the highest increase in calcium signal was observed, and calcium response was likely due to inflow of calcium as well as intracellular signaling via the inositol trisphosphate (IP3) pathway. Recently, El-Sayed et al (Ali et al, 2017) demonstrated that AuNPs with integrin-targeting properties could inhibit cancer cell migration through affecting cytoskeletal proteins. Arg-Gly-Asp (RGD) peptide-functionalized gold nanorods (AuNRs) were fabricated and further activated with 808-nm near-infrared (NIR) light to generate heat for photothermal therapy.…”

“…For cell adhesion, the number of cells adhered on plates gradually increased with decreasing particle AR, and the expression of adhesion molecules in cells treated with MSNs decreased with increasing particle AR. For cytoskeleton, when A375 cells incubated with 0.1 mg/ml NS100 or NSR240, F-actin proteins Changes in the cell shape using DIC images before and after AuNR or NIR treatments (Ali et al, 2017). Reprinted with permission from Ali et al (2017).…”

“…For cytoskeleton, when A375 cells incubated with 0.1 mg/ml NS100 or NSR240, F-actin proteins Changes in the cell shape using DIC images before and after AuNR or NIR treatments (Ali et al, 2017). Reprinted with permission from Ali et al (2017). Copyright (2017) PNAS.…”

Agriculture As Producer of World Cancer Epidemic

“…Although the treatment is still in the research phase, the team sees it being used for head, neck, breast and skin cancers with direct local injections. They also suspect they would be able to treat deeper cancer using a fiber optic or endoscopic laser [11].…”

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“…They also suspect they would be able to treat deeper cancer using a fiber optic or endoscopic laser [11].…”