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1.
Biochim Biophys Acta Mol Cell Res ; 1867(5): 118676, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32044386

RESUMO

In egress routes of malignancy, cancer cells are constantly subjected to shear stress imposed by blood/lymph flow. Increasing evidence points toward the regulatory roles of shear stress in tumor cell adhesion and motility. Although it is known that integrin endocytic trafficking governs focal adhesion (FA) turnover and cell migration, the effect and biological consequences of low shear stress (LSS) on integrin trafficking remain unclear. Here, we identified the critical role of integrin ß1 trafficking and caveolin-1 (Cav-1) mediated endocytosis in LSS-induced cell directional migration. LSS altered the distribution of integrin ß1 in MDA-MB-231 cells and significantly promoted its internalization and recycling, which in turn facilitated FA turnover and directional cell migration. Furthermore, LSS induced cytoskeleton remodeling, which was required for internalization of integrin ß1. LSS down-regulated the acetylation level of microtubules (MTs) via activating ROCK/HDAC6 pathway, resulting in elevation of MTs dynamics, Cav-1 motility, and Cav-1-dependent integrin ß1 recycling. We also showed that high HDAC6 expression was a ROCK-dependent prognostic factor, which was correlated with poor outcomes in breast cancer patients. Taken together, these results defined a novel mechanism by which LSS enhanced integrin ß1 trafficking via actin cytoskeleton remodeling and ROCK/HDAC6 mediated deacetylation of MTs, thereby promoting FAs turnover and directional cell migration.

2.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165625, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785406

RESUMO

One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems.

3.
ACS Appl Mater Interfaces ; 11(47): 43865-43878, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31684723

RESUMO

To realize precise tumor therapy, a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions is necessary. Herein, we fabricated a hybrid micelle (HM) utilizing two amphiphilic diblock copolymers, polyethylenimine-polycaprolactone (PEI-PCL) and diethylenetriaminepentaacetic acid gadolinium(III)  (Gd-DTPA)-conjugated polyethyleneglycol-polycaprolactone (Gd-PEG-PCL), to codeliver the small-molecule chemotherapy drugs doxorubicin (Dox) and microRNA-34a (miR-34a), denoted as Gd-HM-Dox/34a. Conjugating Gd-DTPA on the surface of hybrid micelles, leading the relaxation rate of Gd-DTPA increased more than 1.4 times (13.6 mM-1 S-1). Furthermore, hybrid micelles enhanced the ability of miR-34a to escape from lysosomes/endosomes and Dox release to the nucleus. In addition, the released miR-34a subsequently downregulates Bcl-2, cyclin D1, CDK6, and Bax expression and inhibits proliferation and migration of MDA-MB-231 breast cancer cells. Moreover, the suitable micelle size improved the penetration of Dox into three-dimensional (3D) multicellular spheroids compared with Gd-HM-Dox and Free Dox, generating efficient cell killing in the 3D multicellular spheroids. Furthermore, the Gd-HM-Dox/34a exhibited augmented accumulation in the tumor tissue, which improved the magnetic resonance (MR) imaging contrast of solid tumors and enhanced the combined efficiency of chemotherapeutic drugs Dox and therapeutic gene miR-34a in suppressing tumor growth on MDA-MB-231 tumor-bearing mice. Therefore, we established a hybrid micelle to offer a promising theranostic approach that inhibits tumor growth and enhances MR imaging.

4.
Theranostics ; 9(20): 5784-5796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534519

RESUMO

Background & Aims: The use of antisense oligonucleotide-based nanosystems for the detection and regulation of tumor-related gene expression is thought to be a promising approach for cancer diagnostics and therapies. Herein, we report that a cubic-shaped iron oxide nanoparticle (IONC) core nanobeacon is capable of delivering an HSP90α mRNA-specific molecular beacon (HSP90-MB) into living cells and enhancing T 2-weighted MR imaging in a tumor model. Methods: The nanobeacons were built with IONC, generation 4 poly(amidoamine) dendrimer (G4 PAMAM), Pluronic P123 (P123) and HSP90-MB labeled with a quencher (BHQ1) and a fluorophore (Alexa Fluor 488). Results: After internalization by malignant cells overexpressing HSP90α, the fluorescence of the nanobeacon was recovered, thus distinguishing cancer cells from normal cells. Meanwhile, MB-mRNA hybridization led to enzyme activity that degraded DNA/RNA hybrids and resulted in downregulation of HSP90α at both the mRNA and protein levels. Furthermore, the T 2-weighted MR imaging ability of the nanobeacons was increased after PAMAM and P123 modification, which exhibited good biocompatibility and hemocompatibility. Conclusions: The nanobeacons show promise for applicability to tumor-related mRNA detection, regulation and multiscale imaging in the fields of cancer diagnostics and therapeutics.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30915142

RESUMO

Cryptotanshinone (CTS) was reported to repress a variety of systemic inflammation and alleviate cardiac fibrosis, but it is still unclear whether CTS could prevent radiation-induced lung injury (RILI). Here, we investigated the effects and underlying mechanisms of CTS on a RILI rat model. Our data revealed that CTS could efficiently preserve pulmonary function in RILI rats and reduce early pulmonary inflammation infiltration elicited, along with marked decreased levels of IL-6 and IL-10. Moreover, we found that CTS is superior to prednisone in attenuating collagen deposition and pulmonary fibrosis, in parallel with a marked drop of HYP (a collagen indicator) and α-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-ß1 and NOX-4 expressions, while enhancing the levels of antifibrotic enzyme MMP-1 in lung tissues. It is noteworthy that CTS treatment, in consistent with trichrome staining analysis, exhibited a clear advantage over PND in enhancing MMP-1 levels. However, CTS exhibited little effect on CTGF activation and on COX-2 suppression. Finally, CTS treatment significantly mitigated the radiation-induced activation of CCL3 and its receptor CCR1. In summary, CTS treatment could attenuate RILI, especially pulmonary fibrosis, in rats. The regulation on production and release of inflammatory or fibrotic factors IL-6, IL-10, TGF-ß1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.

7.
Acta Biomater ; 88: 86-101, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771534

RESUMO

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM stiffness in cancer is well known. However, the biomechanical behavior of tumor cells and the underlying mechanotransduction pathways remain unclear. Here, we used polyacrylamide (PAA) substrates to simulate tissue stiffness at different progress stages of breast cancer in vitro, and we observed that moderate substrate stiffness promoted breast cancer cell motility. The substrate stiffness directly activated integrin ß1 and focal adhesion kinase (FAK), which accelerate focal adhesion (FA) maturation and induce the downstream cascades of intracellular signals of the RhoA/ROCK pathway. Interestingly, the differential regulatory mechanism between two ROCK isoforms (ROCK1 and ROCK2) in cell motility and mechanotransduction was clearly identified. ROCK1 phosphorylated the myosin regulatory light chain (MRLC) and facilitated the generation of traction force, while ROCK2 phosphorylated cofilin and regulated the cytoskeletal remodeling by suppressing F-actin depolymerization. The ROCK isoforms differentially regulated the pathways of RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin in a coordinate fashion to modulate breast cancer cell motility in a substrate stiffness-dependent manner through integrin ß1-activated FAK signaling. Our findings provide new insights into the mechanisms of matrix mechanical property-induced cancer cell migration and malignant behaviors. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and tumor cellular motility by using polyacrylamide (PAA) substrates to simulate the stages in vivo of breast cancer. The results elucidated the different regulatory roles between the two ROCK isoforms in cell motility and demonstrated that stiff substrate (38 kPa) mediated RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin pathways through integrin ß1-FAK activation and eventually promoted directional migration. Our discoveries would have significant implications in the understanding of the interaction between cancer cells and tumor microenvironments, and hence, it might provide new insights into the metastasis inhibition, which could be an adjuvant way of cancer therapy.

8.
Mol Pharm ; 16(3): 1367-1384, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776896

RESUMO

A promising approach toward cancer therapy is expected to integrate imaging and therapeutic agents into a versatile nanocarrier for achieving improved antitumor efficacy and reducing the side effects of conventional chemotherapy. Herein, we designed a poly(d,l-lactic- co-glycolic acid) (PLGA)-based theranostic nanoplatform using the double emulsion solvent evaporation method (W/O/W), which is associated with bovine serum albumin (BSA) modifications, to codeliver indocyanine green (ICG), a widely used near-infrared (NIR) dye, and doxorubicin (Dox), a chemotherapeutic drug, for dual-modality imaging-guided chemo-photothermal combination cancer therapy. The resultant ICG/Dox co-loaded hybrid PLGA nanoparticles (denoted as IDPNs) had a diameter of around 200 nm and exhibited excellent monodispersity, fluorescence/size stability, and biocompatibility. It was confirmed that IDPNs displayed a photothermal effect and that the heat induced faster release of Dox, which led to enhanced drug accumulation in cells and was followed by their efficient escape from the lysosomes into the cytoplasm and drug diffusion into the nucleus, resulting in a chemo-photothermal combinatorial therapeutic effect in vitro. Moreover, the IDPNs exhibited a high ability to accumulate in tumor tissue, owing to the enhanced permeability and retention (EPR) effect, and could realize real-time fluorescence/photoacoustic imaging of solid tumors with a high spatial resolution. In addition, the exposure of tumor regions to NIR irradiation could enhance the tumor penetration ability of IDPNs, almost eradicating subcutaneous tumors. In addition, the inhibition rate of IDPNs used in combination with laser irradiation against EMT-6 tumors in tumor-bearing nude mice (chemo-photothermal therapy) was approximately 95.6%, which was much higher than that for chemo- or photothermal treatment alone. Our study validated the fact that the use of well-defined IDPNs with NIR laser treatment could be a promising strategy for the early diagnosis and passive tumor-targeted chemo-photothermal therapy for cancer.


Assuntos
Terapia Combinada/métodos , Doxorrubicina/química , Verde de Indocianina/química , Raios Infravermelhos/uso terapêutico , Nanopartículas/química , Neoplasias/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soroalbumina Bovina/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Temperatura Alta , Verde de Indocianina/efeitos adversos , Verde de Indocianina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Nanopartículas/efeitos adversos , Nanopartículas/metabolismo , Imagem Óptica , Fototerapia/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/efeitos adversos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Soroalbumina Bovina/efeitos adversos , Soroalbumina Bovina/metabolismo , Distribuição Tecidual , Resultado do Tratamento
9.
BMC Complement Altern Med ; 18(1): 250, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30200948

RESUMO

BACKGROUND: Angiogenesis is a pathobiological hallmark of gastric cancer. However, rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Weipixiao (WPX), a Chinese herbal preparation, is proved clinically effective in treating GPL. Here, we evaluated WPX's anti-angiogenic potential for GPL, and also investigated the possibility of its anti-angiogenic mechanisms. METHODS: HPLC analysis was applied to screen the major chemical components of WPX. After modeling N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL in male Sprague-Dawley rats, different doses of WPX were administrated orally for 10 weeks. Next, we performed histopathological examination using routine H&E staining and HID-AB-PAS staining. In parallel, we assessed angiogenesis revealed by microvessel density (MVD) using CD34 immunostaining, and subsequently observe microvessel ultrastructure in gastric mucosa under Transmission Electron Microscope. Finally, we detect expression of angiogenesis-associated markers VEGF and HIF-1α using immunohistochemistry. Moreover, mRNA expressions of ERK1, ERK2, Cylin D1 as well as HIF-1α in gastric mucosa were determined by quantitative real-time reverse transcription- polymerase chain reaction. RESULTS: We observed the appearance of active angiogenesis in GPL rats, and demonstrated that WPX could reduce microvascular abnormalities and attenuate early angiogenesis in most of GPL specimens with a concomitant regression of most intestinal metaplasia (IM) and a portion of gastric epithelial dysplasia (GED). In parallel, WPX could suppress HIF-1α mRNA expression (P < 0.01) as well as protein expression (although without statistical significance), and could markedly inhibit VEGF protein expression in GPL rats. Mechanistically, WPX intervention, especially at low dose, caused a significant decrease in the ERK1 and Cylin D1 mRNA levels. However, WPX might probably have no regulatory effect on ERK2 amplification. CONCLUSIONS: WPX could attenuate early angiogenesis and temper microvascular abnormalities in GPL rats. This might be partly achieved by inhibiting on the angiogenesis-associated markers HIF-1α and VEGF, and on the ERK1/Cylin D1 aberrant activation.


Assuntos
Inibidores da Angiogênese/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Neovascularização Patológica , Neoplasias Gástricas/irrigação sanguínea , Estômago/efeitos dos fármacos , Animais , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ratos , Ratos Sprague-Dawley , Estômago/irrigação sanguínea , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
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