RESUMEN
Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.
Asunto(s)
Lisina , Neoplasias Pancreáticas , Humanos , Lisina/metabolismo , Histonas/metabolismo , Glucólisis , Procesamiento Proteico-PostraduccionalRESUMEN
Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors. The involvement of N-myc (and STAT) interactor (NMI) and its possible functional mechanisms in HCC progression still remain to be elucidated. In this study, we found that NMI was overexpressed in metastatic HCC cell lines compared with non-metastatic ones; and the expression levels of NMI in the HCC samples with metastasis were higher than that in the non-metastatic specimens. Furthermore, NMI depletion significantly decreased HCC cell proliferation and invasiveness in vitro, and also inhibited tumor growth and lung metastasis in vivo in nude mice models bearing human HCC. By contrast, NMI stable overexpression can enhance the malignant behaviors obviously. Moreover, we further verified that NMI promotes the expression of BDKRB2 and mediates the activation of MAPK/ERK signaling pathway according to the bidirectional perturbations of NMI expression in vivo or in vitro of HCC. Taken together, NMI is a pro-metastatic molecule and partially responsible for HCC tumor growth and motility. NMI could improve its downstream target BDKRB2 expression to induce ERK1/2 activation, and thereby further evoke malignant progression of HCC.
Asunto(s)
Carcinoma Hepatocelular/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/genética , Sistema de Señalización de MAP Quinasas , Receptor de Bradiquinina B2/genética , Animales , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Interferencia de ARN , Tratamiento con ARN de Interferencia/métodos , Receptor de Bradiquinina B2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
To better understand the pathophysiologic mechanisms underlying Guillain-Barré syndrome (GBS), Comparative proteomic analysis of cerebrospinal fluid (CSF) between patients with GBS (the experiment group) and control subjects suffering from other neurological disorders (the control group) was carried out using two-dimensional gel electrophoresis (2-DE) technique, in combination with matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) and database searching to determine abnormal CSF proteins in GBS patients. Image analysis of 2-DE gels silver stained revealed that 10 protein spots showed significant differential expression between the two groups of CSF samples. The expression of cystatin C, transthyretin, apolipoprotein E and heat shock protein 70 were decreased. However, haptoglobin, alpha-1-antitrypsin, apolipoprotein A-IV and neurofilaments were elevated. The subsequent ELISA measured the concentration of cystatin C and confirmed the result of the proteomic analysis. These identified proteins may be involved in the pathophysiological process of GBS and call for further studying the role of these proteins in the pathogenesis of the disease.