Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms. Results: Acquired resistance to FK866 was independent of NAMPT mutations but rather was based on a shift towards a glycolytic metabolism and on lactate dehydrogenase A (LDHA) activity. In addition, resistant CCRF-CEM cells, which exhibit high quinolinate phosphoribosyltransferase (QPRT) activity, also exploited amino acid catabolism as an alternative source for NAD+ production, becoming addicted to tryptophan and glutamine and sensitive to treatment with the amino acid transport inhibitor JPH203 and with L-asparaginase, which affects glutamine exploitation. Vice versa, in line with their low QPRT expression, FK866-resistant MDA MB231 did not rely on amino acids for their resistance phenotype. Conclusions: Our study identifies novel mechanisms of resistance to NAMPT inhibition, which may be useful to design more rational strategies for targeting cancer metabolism

Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation

During phagocytosis, the phosphoinositide content of the activated membrane decreases sharply, as does the associated surface charge, which attracts polycationic proteins. The cytosolic leaflet of the plasma membrane is enriched in phosphatidylserine (PS); however, a lack of suitable probes has precluded investigation of the fate of this phospholipid during phagocytosis. We used a recently developed fluorescent biosensor to monitor the distribution and dynamics of PS during phagosome formation and maturation. Unlike the polyphosphoinositides, PS persists on phagosomes after sealing even when other plasmalemmal components have been depleted. High PS levels are maintained through fusion with endosomes and lysosomes and suffice to attract cationic proteins like c-Src to maturing phagosomes. Phagocytic vacuoles containing the pathogens Legionella pneumophila and Chlamydia trachomatis, which divert maturation away from the endolysosomal pathway, are devoid of PS, have little surface charge, and fail to recruit c-Src. These findings highlight a function for PS in phagosome maturation and microbial killing

Etude du role des reactions de phosphorylation au cours de l'activation du lymphocyte T : stimulation precoce d'une activite serine kinase et d'une activite tyrosine kinase

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

A pollen-climate calibration from western Patagonia for palaeoclimatic reconstructions

International audiencePalaeoecological studies of sediment records in the western margins of southern South America have revealed the vegetation dynamic under the influence of major regional climate drivers such as the Southern Westerly Winds, Southern Annular Mode and the El Niño Southern Oscillation phenomenon. Despite the substantial number of palynological records that have been studied, very few quantitative pollen-based climate reconstructions using surface sample have been attempted. In this context, our objective is first to investigate the modern pollen-vegetation-climate relationships in the western Patagonian region. Results reveal that the modern pollen dataset reflects the main vegetation types and that summer precipitation and winter temperature represent the main climate parameters controlling vegetation distribution. Secondly using this pollen-climate dataset we evaluate and compare the performance of two models (Weighted Averaging Partial Least Squares and Modern Analog Technique). We applied these models to perform climate reconstructions from two oceanic pollen records from western Patagonia. Compared with independent climate indicators, our pollen pollen-inferred climate reconstructions reveal the same overall trends showing the potential of pollen-climate transfer functions applied to this region. This study provides much needed data for quantitative climate reconstructions in South America which still need to be improved by enlarging the modern pollen dataset

Saccharomyces boulardii Interferes with Enterohemorrhagic Escherichia coli-Induced Signaling Pathways in T84 Cells

Enterohemorrhagic Escherichia coli (EHEC) infections are associated with the modification of tight-junction permeability and synthesis of proinflammatory cytokine interleukin-8 (IL-8). In a previous study, it was demonstrated that EHEC-induced IL-8 secretion is due to the involvement of the mitogen-activated protein kinase (MAPK), AP-1, and NF-κB pathways. In this study, we investigated the effect of the yeast Saccharomyces boulardii on EHEC infection in T84 cells. For this purpose, cells were (i) incubated with bacteria and yeast at the same time or (ii) incubated overnight with yeast cells that were maintained during infection or eliminated by several washes before infection. Coincubation is sufficient to maintain the transmonolayer electrical resistance (TER) of EHEC-infected cells, whereas the preincubation of cells with the yeast without elimination of the yeast during infection is necessary to significantly decrease IL-8 secretion. We thus analyzed the mechanisms of S. boulardii action. We showed that S. boulardii has no effect on EHEC growth or on EHEC adhesion. Kinetics studies revealed that EHEC-induced myosin light chain (MLC) phosphorylation precedes the decrease of TER. ML-7, an MLC kinase inhibitor, abolishes the EHEC-induced MLC phosphorylation and decrease of TER. Studies show that S. boulardii also abolishes EHEC-induced MLC phosphorylation. We demonstrated that the preincubation of cells with S. boulardii without washes before EHEC infection inhibits NF-κB DNA binding activity, phosphorylation and degradation of IκB-α, and activation of the three members of a MAPK group (extracellular signal-regulated protein kinases 1 and 2, p38, and c-jun N-terminal kinase). These findings demonstrate that S. boulardii exerts a preventive effect on EHEC infection by (i) interfering with one of the transduction pathways implicated in the control of tight-junction structure and (ii) decreasing IL-8 proinflammatory secretion via inhibition of the NF-κB and MAPK signaling pathways in infected T84 cells

Scène pastorale

Appartient à l’ensemble documentaire : 3M000Appartient à l’ensemble documentaire : 3M01

Découverte de Romulus et Rémus (La)

Appartient à l’ensemble documentaire : 3M000Appartient à l’ensemble documentaire : 3M01

Moïse défendant les filles de Jethro

Appartient à l’ensemble documentaire : 3M000Appartient à l’ensemble documentaire : 3M01