Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Language
Publication year range
1.
Clin Exp Immunol ; 203(3): 341-350, 2021 03.
Article in English | MEDLINE | ID: mdl-32961586

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and different degrees of B cell compartment alteration. Memory B cell differentiation requires the orchestrated activation of several intracellular signaling pathways that lead to the activation of a number of factors, such as nuclear factor kappa B (NF-κB) which, in turn, promote transcriptional programs required for long-term survival. The aim of this study was to determine if disrupted B cell differentiation, survival and activation in B cells in CVID patients could be related to defects in intracellular signaling pathways. For this purpose, we selected intracellular readouts that reflected the strength of homeostatic signaling pathways in resting cells, as the protein expression levels of the Bcl-2 family which transcription is promoted by NF-κB. We found reduced Bcl-2 protein levels in memory B cells from CVID patients. We further explored the possible alteration of this crucial prosurvival signaling pathway in CVID patients by analysing the expression levels of mRNAs from anti-apoptotic proteins in naive B cells, mimicking T cell-dependent activation in vitro with CD40L and interleukin (IL)-21. BCL-XL mRNA levels were decreased, together with reduced levels of AICDA, after naive B-cell activation in CVID patients. The data suggested a molecular mechanism for this tendency towards apoptosis in B cells from CVID patients. Lower Bcl-2 protein levels in memory B cells could compromise their long-term survival, and a possible less activity of NF-κB in naive B cells, may condition an inabilityto increase BCL-XL mRNA levels, thus not promoting survival in the germinal centers.


Subject(s)
B-Lymphocytes/metabolism , Common Variable Immunodeficiency/genetics , Gene Expression , Proto-Oncogene Proteins c-bcl-2/genetics , Apoptosis/genetics , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cells, Cultured , Common Variable Immunodeficiency/metabolism , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Flow Cytometry , Humans , Immunologic Memory/immunology , Lymphocyte Activation/genetics , NF-kappa B/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , bcl-X Protein/genetics , bcl-X Protein/metabolism
2.
Oncogene ; 32(10): 1274-83, 2013 Mar 07.
Article in English | MEDLINE | ID: mdl-22543588

ABSTRACT

Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P=0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/pharmacology , DNA Methylation , Insulin-Like Growth Factor Binding Protein 3/metabolism , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/metabolism , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 3/biosynthesis , Insulin-Like Growth Factor Binding Protein 3/deficiency , Insulin-Like Growth Factor Binding Protein 3/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Phosphorylation , Promoter Regions, Genetic , Proto-Oncogene Proteins c-akt/genetics , Receptor, IGF Type 1/genetics , Signal Transduction , Transfection
3.
Clin. transl. oncol. (Print) ; 13(6): 363-367, jun. 2011. ilus, tab
Article in English | IBECS | ID: ibc-124675

ABSTRACT

Metformin is a biguanine, the most widely used antidiabetic drug for the treatment of type 2 diabetes. Some studies suggest that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. Metformin activates the AMP-activated protein kinase (AMPK) pathway, a major sensor of the energy status of the cell and an inhibitor of mammalian target of rapamycin (mTOR) catalytic activity, inducing a decrease in blood glucose by decreasing hepatic gluconeogenesis and stimulating glucose uptake in the muscle. Some preclinical data supports the inhibition of tumour cancer cell growth associated with mTOR inhibition and a decrease in phosphorylation of S6K, rpS6 and 4E-BP1. Here we have summarised some of the preclinical data and data of many clinical trials that are exploring the true value of metformin for cancer patients, mainly breast and prostate cancer (AU)


Subject(s)
Humans , Animals , Male , Female , Antineoplastic Agents/therapeutic use , Metformin/therapeutic use , Neoplasms/drug therapy , Hypoglycemic Agents/therapeutic use , Prognosis
SELECTION OF CITATIONS
SEARCH DETAIL
...