10 research outputs found

    E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

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    The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis

    E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells

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    Deletion of E4F1 inflicts mitochondrial damage and oxidative stress on murine and human myeloid leukemia cells but not healthy macrophages

    RÎle du suppresseur de tumeurs p53 dans le contrÎle du métabolisme

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    International audienceThe p53 tumor suppressor is an essential downstream effector of various cellular stress response pathways that is functionally inactivated in most, if not all, tumors. Since its discovery more than 30 years ago, its role in the control of cell proliferation, senescence and cell survival has been widely described. However, growing evidences from several laboratories indicate that p53 has important transcriptional and non-transcriptional functions in the control of metabolism, including the regulation of glycolysis, glutaminolysis or mitochondrial respiration. Originally identified using in vitro cellular models, this previously underestimated role of p53 has been confirmed in vivo in various genetically engineered mouse models. These recent data suggest that p53 functions in various metabolic pathways significantly contribute to its role in adult tissue homeostasis, aging as well as tumor suppression.Le suppresseur de tumeurs p53 est un mĂ©diateur essentiel des voies de rĂ©ponse cellulaire Ă  des stress de nature trĂšs variĂ©e qui est inactivĂ© dans la majoritĂ© des tumeurs. Au-delĂ  de ses fonctions connues dans le contrĂŽle de la prolifĂ©ration, de la sĂ©nescence ou de la mort cellulaire, des rĂ©sultats rĂ©cents de diffĂ©rents laboratoires indiquent que p53 joue de multiples rĂŽles dans le contrĂŽle du mĂ©tabolisme Ă©nergĂ©tique, et qu’il est lui mĂȘme rĂ©gulĂ© par de nombreux changements mĂ©taboliques. Il est vraisemblable que ces actions de p53, encore mal connues, jouent un rĂŽle important, Ă  la fois pour les fonctions de suppresseur de tumeurs de cette protĂ©ine, mais Ă©galement dans l’homĂ©ostasie tissulaire, ainsi qu’au cours du vieillissement

    RÎle du suppresseur de tumeurs p53 dans le contrÎle du métabolisme

    No full text
    Le suppresseur de tumeurs p53 est un mĂ©diateur essentiel des voies de rĂ©ponse cellulaire Ă  des stress de nature trĂšs variĂ©e qui est inactivĂ© dans la majoritĂ© des tumeurs. Au-delĂ  de ses fonctions connues dans le contrĂŽle de la prolifĂ©ration, de la sĂ©nescence ou de la mort cellulaire, des rĂ©sultats rĂ©cents de diffĂ©rents laboratoires indiquent que p53 joue de multiples rĂŽles dans le contrĂŽle du mĂ©tabolisme Ă©nergĂ©tique, et qu’il est lui mĂȘme rĂ©gulĂ© par de nombreux changements mĂ©taboliques. Il est vraisemblable que ces actions de p53, encore mal connues, jouent un rĂŽle important, Ă  la fois pour les fonctions de suppresseur de tumeurs de cette protĂ©ine, mais Ă©galement dans l’homĂ©ostasie tissulaire, ainsi qu’au cours du vieillissement

    Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer

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    International audienceBACKGROUND:The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells.SCOPE OF REVIEW:We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases.MAJOR CONCLUSIONS:p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression

    Combining the antianginal drug perhexiline with chemotherapy induces complete pancreatic cancer regression in vivo

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    Summary: Pancreatic ductal adenocarcinoma (PDAC) remains one of the human cancers with the poorest prognosis. Interestingly, we found that mitochondrial respiration in primary human PDAC cells depends mainly on the fatty acid oxidation (FAO) to meet basic energy requirements. Therefore, we treated PDAC cells with perhexiline, a well-recognized FAO inhibitor used in cardiac diseases. Some PDAC cells respond efficiently to perhexiline, which acts synergistically with chemotherapy (gemcitabine) in vitro and in two xenografts in vivo. Importantly, perhexiline in combination with gemcitabine induces complete tumor regression in one PDAC xenograft. Mechanistically, this co-treatment causes energy and oxidative stress promoting apoptosis but does not exert inhibition of FAO. Yet, our molecular analysis indicates that the carnitine palmitoyltransferase 1C (CPT1C) isoform is a key player in the response to perhexiline and that patients with high CPT1C expression have better prognosis. Our study reveals that repurposing perhexiline in combination with chemotherapy is a promising approach to treat PDAC

    Dexamethasone in hyperleukocytic acute myeloid leukemia

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    International audiencePatients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; P<0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; P=0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in NPM1-mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with NPM1 mutation

    Mitochondrial MDM2 regulates respiratory complex i activity independently of p53

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    International audienceAccumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production. Recruitment of MDM2 to mitochondria increases during oxidative stress and hypoxia. Accordingly, mice lacking MDM2 in skeletal muscles exhibit higher MT-ND6 levels, enhanced complex I activity, and increased muscular endurance in mild hypoxic conditions. Furthermore, increased mitochondrial MDM2 levels enhance the migratory and invasive properties of cancer cells. Collectively, these data uncover a previously unsuspected function of the MDM2 oncoprotein in mitochondria that play critical roles in skeletal muscle physiology and may contribute to tumor progression
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