Glycolytic Reprogramming Through PCK2 Regulates Tumor Initiation of Prostate Cancer Cells

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein acetylation. Our data suggest PCK2 promotes tumor initiation by lowering acetyl-CoA level through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate tumors

Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition

Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin. (C) 2015 Elsevier Ltd. All rights reserved.Ministerio de Ciencia e Innovacion, Spain [SAF2011-25726]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)-Generalitat de Catalunya [2014SGR1017]; Ministerio de Economia y Competitividad, Spain [SAF2014-56059-R]; Fundacao para a Ciencia e a Tecnologia (FCT) Research Center [UID/BIM/04773/2013CBMR 1334]; National Institute of Health, USA [1R01CA118434-01A2, 1P01CA163223-01A1]; National Science Foundation, USA [EPS-0447479]; FCT [SFRH/BPD/84634/2012]; prize ICREA Academia for excellence in research; ICREA Foundation-Generalitat de Cataluny

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Phytoremédiation : influence des ligands naturels sur la mobilisation et l'accumulation de métaux par les plantes: Cas de plants de blé modifiés génétiquement

International audiencePhytoremediation is a remediation process that can be used to clean up soils contaminated with heavy metals. Three main approaches can be utilized: phytoextraction, phytovolatilization, and phytostabilization, each of them exploiting the natural ability of plants to accumulate or exclude/stabilize elements from soils. To implement this alternative technology, a better understanding of the various processes controlling metal mobilization, uptake and sequestration by plants is needed. Metal chelation is recognized as an important factor, regulating to a large extent metals solubility and availability to plants. Natural ion chelators (or MIL: Metal Ion Ligand), produced in the tissus or exuded by the roots, are involved in these phenomena, but their exact nature and the various mechanisms have to be précised. We investigated the influence of elevated metals concentrations on MIL profiles and on metal accumulation in the plant tissues in wheat (Triticum aestivum L.CV Chinese Spring) genetically modified by disomic addition of wheatgrass (Lophopyrum elogatum L.) chromosomes. Qualitative and quantitative determinations of MIL profiles are realised by GC-MS and RMN 1-D and 2-D. Concentrations of metals in the tissues are obtained by energy dispersive X-ray fluorescence spectroscopy. Correlations between some metals (ie, Fe, Zn, Mn) and some MIL exuded or present in the roots (ie, acetate), depending on the various genotypes, have been observed. The results suggest possible chromosomal location(s) of gene(s) involved in mobilization and/or sequestration of metals.La phytoremédiation est un procédé de traitement des sols applicable in situ pour traiter des pollutions métalliques. L'amélioration de ce type de procédé passe par une meilleure compréhension des processus de mobilisation, d'absorption et de séquestration des métaux par les plantes. La chélation est reconnue comme un phénomène important régulant la solubilité, la biodisponibilité et le stockage interne des métaux. L'influence de teneurs élevées en métaux sur les profils d'agents chélatants produits par les plantes a été étudiée sur des plants de blés modifiés génétiquement. L'ensemble des résultats suggère de possibles localisations de gènes gouvernant la mobilisation et la séquestration des métaux par ces plantes