RESUMO
CCAAT/enhancer-binding protein δ (C/EBPδ) recently emerged as an essential player in the inflammatory response to bacterial infections. C/EBPδ levels increase rapidly after a proinflammatory stimulus, and increasing C/EBPδ levels seem to be indispensable for amplification of the inflammatory response. Here we aimed to elucidate the role of C/EBPδ in host defense in community-acquired pneumococcal pneumonia. We show that C/EBPδ(-/-) mice are relatively resistant to pneumococcal pneumonia, as indicated by delayed and reduced mortality, diminished outgrowth of pneumococci in lungs, and reduced dissemination of the infection. Moreover, expression of platelet-activating factor receptor (PAFR), which is known to potentiate bacterial translocation of gram-positive bacteria, was significantly reduced during infection in C/EBPδ(-/-) mice compared with WT controls. Importantly, cell stimulation experiments revealed that C/EBPδ potentiates PAFR expression induced by lipoteichoic acid and pneumococci. Thus, C/EBPδ exaggerates bacterial dissemination during Streptococcus pneumoniae-induced pulmonary infection, suggesting an important role for PAFR-dependent bacterial translocation.
Assuntos
Proteína delta de Ligação ao Facilitador CCAAT/imunologia , Regulação da Expressão Gênica/fisiologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Pneumonia Pneumocócica/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Western Blotting , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Técnicas Histológicas , Humanos , Luciferases , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Permeabilidade , Pneumonia Pneumocócica/microbiologia , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não ParamétricasRESUMO
Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid with potent anticancer capacity that targets the mitochondrial pathway of apoptosis. BetA has a broad efficacy in vitro against prevalent cancer types, including lung, colorectal, prostate, cervix and breast cancer, melanomas, neuroblastomas, and leukemias. The cytotoxic effects of the compound against healthy cells are minimal, rendering BetA a promising potential anticancer drug. However, because of the weak hydrosolubility of BetA, it has been difficult to study its efficacy in vivo and a pharmaceutical formulation is not yet available. We report the development of a liposome formulation of BetA and show its successful application in mice. Large liposomes, assembled without cholesterol to reduce their rigidity, efficiently incorporated BetA. Nude mice xenografted with human colon and lung cancer tumors were treated intravenously with the BetA-containing liposomes. Tumor growth was reduced to more than 50% compared with the control treatment, leading to an enhanced survival of the mice. Oral administration of the liposomal formulation of BetA also slowed tumor growth. Any signs of systemic toxicity caused by BetA treatment were absent. Thus, liposomes are an efficient formulation vehicle for BetA, enabling its preclinical development as a nontoxic compound for the treatment of cancers.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Triterpenos/administração & dosagem , Administração Oral , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Estabilidade de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Lipossomos/química , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Triterpenos Pentacíclicos , Rodaminas , Triterpenos/química , Triterpenos/toxicidade , Ácido BetulínicoRESUMO
Protease activated receptor-1 (PAR1) expression is associated with disease progression and overall survival in a variety of cancers. However, the importance of tumor cell PAR1 in pancreatic ductal adenocarcinomas (PDAC) remains unexplored. Utilizing orthotopic models with wild type and PAR1-targeted PDAC cells, we show that tumor cell PAR1 negatively affects PDAC growth, yet promotes metastasis. Mechanistically, we show that tumor cell-specific PAR1 expression correlates with mesenchymal signatures in PDAC and that PAR1 is linked to the maintenance of a partial mesenchymal cell state. Indeed, loss of PAR1 expression results in well-differentiated pancreatic tumors in vivo, with enhanced epithelial characteristics both in vitro and in vivo. Taken together, we have identified a novel growth inhibitory role of PAR1 in PDAC, which is linked to the induction, and maintenance of a mesenchymal-like phenotype. The recognition that PAR1 actively limits pancreatic cancer cell growth suggest that the contributions of PAR1 to tumor growth differ between cancers of epithelial origin and that its targeting should be applied with care.