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1.
Molecules ; 25(17)2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32872164

RESUMO

In recent years, lipid metabolism has garnered significant attention as it provides the necessary building blocks required to sustain tumor growth and serves as an alternative fuel source for ATP generation. Fatty acid synthase (FASN) functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors with lipogenic phenotypes. Accumulating evidence has shown that it is capable of rewiring tumor cells for greater energy flexibility to attain their high energy requirements. This multi-enzyme protein is capable of modulating the function of subcellular organelles for optimal function under different conditions. Apart from lipid metabolism, FASN has functional roles in other cellular processes such as glycolysis and amino acid metabolism. These pivotal roles of FASN in lipid metabolism make it an attractive target in the clinic with several new inhibitors currently being tested in early clinical trials. This article aims to present the current evidence on the emergence of FASN as a target in human malignancies.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintases/metabolismo , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ácido Graxo Sintases/antagonistas & inibidores , Ácido Graxo Sintases/genética , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/etiologia
2.
Blood ; 124(19): 2973-82, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25139349

RESUMO

It is known that cells within the inflammatory background in classical Hodgkin lymphoma (cHL) provide signals essential for the continual survival of the neoplastic Hodgkin and Reed-Sternberg (HRS) cells. However, the mechanisms underlying the recruitment of this inflammatory infiltrate into the involved lymph nodes are less well understood. In this study, we show in vitro that HRS cells secrete lymphotoxin-α (LTα) which acts on endothelial cells to upregulate the expression of adhesion molecules that are important for T cell recruitment. LTα also enhances the expression of hyaluronan which preferentially contributes to the recruitment of CD4(+) CD45RA(+) naïve T cells under in vitro defined flow conditions. Enhanced expression of LTα in HRS cells and tissue stroma; and hyaluronan on endothelial cells are readily detected in involved lymph nodes from cHL patients. Our study also shows that although NF-κB and AP-1 are involved, the cyclooxygenase (COX) pathway is the dominant regulator of LTα production in HRS cells. Using pharmacological inhibitors, our data suggest that activity of COX1, but not of COX2, directly regulates the expression of nuclear c-Fos in HRS cells. Our findings suggest that HRS cell-derived LTα is an important mediator that contributes to T cell recruitment into lesional lymph nodes in cHL.


Assuntos
Linfócitos T CD4-Positivos/citologia , Comunicação Celular/imunologia , Células Endoteliais/citologia , Doença de Hodgkin/metabolismo , Linfotoxina-alfa/metabolismo , Células de Reed-Sternberg/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Doença de Hodgkin/imunologia , Doença de Hodgkin/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptores de Hialuronatos/imunologia , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/imunologia , Ácido Hialurônico/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Linfotoxina-alfa/imunologia , Células de Reed-Sternberg/imunologia , Células de Reed-Sternberg/metabolismo
3.
Front Cell Dev Biol ; 9: 673647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095144

RESUMO

Posttranslational modification of proteins with lipid moieties is known as protein lipidation. The attachment of a lipid molecule to proteins endows distinct properties, which affect their hydrophobicity, structural stability, localization, trafficking between membrane compartments, and influences its interaction with effectors. Lipids or lipid metabolites can serve as substrates for lipidation, and the availability of these lipid substrates are tightly regulated by cellular metabolism. Palmitoylation and myristoylation represent the two most common protein lipid modifications, and dysregulation of protein lipidation is strongly linked to various diseases such as metabolic syndromes and cancers. In this review, we present recent developments in our understanding on the roles of palmitoylation and myristoylation, and their significance in modulating cancer metabolism toward cancer initiation and progression.

4.
Cancers (Basel) ; 13(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805973

RESUMO

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review.

5.
Front Cell Dev Biol ; 9: 706143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34291056

RESUMO

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1 -/- mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1 -/- mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.

6.
Commun Biol ; 4(1): 370, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854168

RESUMO

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.


Assuntos
Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazinas/farmacologia , Células A549 , Animais , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Terapia de Alvo Molecular , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA-Seq , Análise de Célula Única , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Commun ; 11(1): 1556, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214092

RESUMO

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Fenótipo , Fosforilação/efeitos dos fármacos , Polimorfismo Genético , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/química , Receptor ErbB-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Theranostics ; 9(21): 6157-6174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534543

RESUMO

Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.


Assuntos
Antineoplásicos/farmacologia , Atorvastatina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Caveolina 1/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Caveolina 1/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Glucose/metabolismo , Transportador de Glucose Tipo 3/genética , Humanos , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Terapia de Alvo Molecular , Mutação
9.
ACS Sens ; 3(9): 1647-1655, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30095245

RESUMO

Leucine-rich alpha-2-glycoprotein-1 (Lrg1) is an emerging biomarker for angiogenesis. Its expression in ocular tissues is up-regulated in both human patients with proliferative diabetic retinopathy and rodent models of pathological angiogenesis. However, there is no existing sensor that allows visualization and monitoring of Lrg1 expression noninvasively and in real time. Herein, we report a nucleic acid-gold nanorod-based nanosensor for the noninvasive monitoring of cellular Lrg1 expression in angiogenesis. Specifically, this platform is constructed by covalently conjugating molecular beacons onto gold nanorods, which prequench the fluorophores on the molecular beacons. Upon intracellular entry and endosomal escape, the complexes interact with cellular Lrg1 mRNA through hybridization of the loop area of the molecular beacons. This complexation distances the fluorophores from nanorod and restores the prequenched fluorescence. The reliability of this platform is confirmed by examining the increased Lrg1 expression in migrating keratinocytes and the Lrg1 gene changes in different postnatal stages of mouse retinal vasculature growth in the mouse retina model.


Assuntos
Glicoproteínas/genética , Ouro/química , Nanotubos/química , Neovascularização Patológica/metabolismo , RNA Mensageiro/análise , Animais , Carbocianinas/química , Linhagem Celular , Fluorescência , Corantes Fluorescentes/química , Ouro/toxicidade , Humanos , Sequências Repetidas Invertidas , Camundongos Endogâmicos C57BL , Nanotubos/toxicidade , Hibridização de Ácido Nucleico , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/toxicidade , Retina/química , Regulação para Cima
10.
Nat Protoc ; 10(10): 1459-73, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26334866

RESUMO

The mouse fetal metatarsal provides a unique tool for studying angiogenesis. In comparison with other commonly used in vitro or ex vivo angiogenesis assays, vessel outgrowth from mouse fetal metatarsals is more representative of sprouting angiogensis in vivo. It allows the analysis of blood vessel growth, and the mechanisms underpinning this process, in a multicellular microenvironment that drives the formation of a robust and complex vascular network in the absence of exogenous growth factors. By labeling different constituents of the vascular structure, it is possible to perform 3D rendering of the spatial interplay between different cellular components and to carry out quantitative analysis of vessel outgrowth. High-resolution imaging permits the visualization of fine structural and cellular details. As the assay involves the use of fetal tissues, it is possible to follow new blood vessel formation in genetically modified mice that are perinatally lethal. The entire process takes 9-13 d. A detailed description of how to set up and perform the assay is described here.


Assuntos
Técnicas de Cultura/métodos , Ossos do Metatarso/irrigação sanguínea , Neovascularização Patológica/patologia , Animais , Modelos Animais de Doenças , Feminino , Feto , Imunofluorescência , Ossos do Metatarso/patologia , Camundongos , Microvasos/patologia , Neovascularização Patológica/genética , Coloração e Rotulagem
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