Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia

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Différenciation des effets antioxydants in vivo et antiprolifératifs ex vivo du lycopène et de la tomate

L'intérêt pour la tomate tient son origine d'études épidémiologiques qui ont mis en évidence une corrélation inverse entre l'ingestion de tomate et/ou de ses produits dérivés et le risque de survenue de maladies cardiovasculaires mais surtout du cancer de la prostate. La couleur rouge de la tomate provient d'un caroténoïde pigment, le lycopène. Ce dernier est un antioxydant puissant de par sa structure chimique faite de doubles liaisons conjuguées qui permettent de neutraliser les espèces oxygénées réactives (EOR). Les EOR peuvent créer des dommages très importants au niveau de l'organisme et notamment contribuer aux processus de cancérisation. Le lycopène possède aussi des effets anticancéreux. Il a été démontré sur différentes lignées cellulaires cancéreuses qu'il pouvait, à des doses supra-nutritionnelles, inhiber la prolifération cellulaire et augmenter l'apoptose. La part de lycopène circulant chez l'homme étant due à 85% à l'ingestion de tomate, l'assimilation de l'effet de la tomate à celui du lycopène paraît logique. Cependant les études d'intervention qui ont comparé les effets de la tomate rouge et du lycopène sur les processus de cancérisation chez le patient ou sur des modèles de carcinogenèse prostatique chez le rat, ont démontré un effet supérieur de la tomate. La tomate contient d'autres carotéloïdes, des vitamines, des polyphénols, des oligoéléments et des fibres qui peuvent avoir aussi des effets protecteurs. De plus, le lycopène donne des métabolites et des produits d'oxydations bioactifs. L'objectif de cette thèse était de différencier l'effet de la tomate et du lycopène sur le stress oxydant in vivo et sur la prolifération cellulaire ex vivo, en utilisant une variété de tomate dépourvue de lycopène, la tomate jaune. In vivo, sur un modèle animal de stress oxydant modéré induit par la voie nutritionnelle, l'impact de complémentations en tomate rouge (STR), tomate jaune (STJ) et lycopène (SL) a été étudié sur les biomarqueurs du stress oxydant. Après avoir validé le modèle de stress oxydant, les STR et STJ ont montré des effets préventifs similaires sur la peroxydation lipidique au niveau du tissu cardiaque. Les STR et STJ ont permis d'améliorer certains marqueurs du stress oxydant circulants comme l'oxyde nitrique et la capacité antioxydante globale du plasma. La SL n'a pas permis de prévenir la peroxydation au niveau du tissu cardiaque ni d'améliorer les biomarqueurs du stress oxydant. Ex vivo, les effets antiprolifératifs des séra issus de l'expérimentation animale précédente ont été étudiés sur des cellules cancéreuses prostatiques exprimant le récepteur aux androgènes (PC3AR). Pour cela les cellules ont été mises en culture dans un milieu contenant ces séra à 10% à la place du sérum de veau fœtal pendant 48 heures. Nos résultats montrent que les séra issus des STR et STJ ont pu permettre la sur-expression de la connexine 43 (Cx43), une protéine qui est sous-exprimée en cas de cancer et dont la régulation entraîne une restauration de la communication intercellulaire et permet une inhibition de la croissance cellulaire. Les effets du sérum issu de la SL n'étaient pas significatifs bien que la concentration en lycopène intracellulaire au bout de 48 heures était identique après traitement avec les séra issus des STR et SL. Par contre, de par les faibles concentrations en micronutriments apportés par les 10% de sérum, aucun effet significatif n'a pu être mis en évidence sur la prolifération cellulaire. Dans un 3ème temps, nous avons essayé d'identifier les métabolites générés par les STR, STJ et SL au niveau des urines des animaux par une analyse en spectrométrie de masse chez les rats sains et soumis à un stress oxydant. Le métabolome urinaire des animaux est modifié de la même manière par les STR et STJ que les animaux soient stressés ou non. De plus, les complémentations en tomate ont permis d'améliorer des métabolites biomarqueurs du stress oxydant. Le lycopène a eu un impact différent sur le métabolome et non bénéfique. En conclusion, la tomate qu'elle contienne ou non du lycopène peut avoir des effets antioxydants ou antiprolifératifs. Dans cette étude, les effets du lycopène sont nuls vis à vis du stress oxydant et moins importants que les STR et la STJ sur l'expression de la connexine 43. L'hypothèse est donc que les autres micronutriments de la tomate, hydrosolubles ou liposolubles, peuvent interagir ensemble pour améliorer les paramètres du stress oxydant, et donc apporter un effet bénéfique plus important que le lycopène seul.The interest for tomato comes from an epidemiological study that pointed out inverse association between tomato and/or tomato processed products ingestion and cardiovascular disease and also prostate cancer risk. The red colour of tomato is given by lycopene, a pigment carotenoid. The latter is a powerful antioxidant molecule thanks to its conjugated double bounds that can quench reactive oxygen species (ROS). ROS can be responsible of oxidative damage and can thereby strongly contribute to carcinogenesis processes. Lycopene has also demonstrated properties against cancer. Indeed, lycopene at supra-physiological concentrations inhibit cellular proliferation and apoptosis on different cancer cell lines. As 85% of circulating lycopene is due to tomato ingestion, tomato effects were assimilated to those of lycopene. However intervention studies aiming at comparing tomato and lycopene effects on carcinogenesis processes in prostate cancer patients or rat models of carcinogenesis, revealed stronger beneficial effect of tomato. Tomato contains other phytomicronutrients such as carotenoids, vitamins, polyphénols, oligoelements and fibres that also may have effects. Furthermore lycopene can generate bioactive metabolites and oxidative products. The goal of this thesis was to differentiate tomato and lycopene effects on oxidative stress in vivo and on cell proliferation ex vivo, by using yellow tomato, a tomato cultivar devoid of lycopene. In vivo, in a rat model of mild nutritional oxidative stress, effects of supplementation with red tomato (SRT), yellow tomato (SYT) and lycopene (SL) were assessed on oxidative stress biomarkers. After oxidative stress model validation, SRT and SYT exhibited similar preventive effect on heart tissue lipid peroxidation. SRT and SYT improved some circulating oxidative stress biomarkers such as nitric oxide and total antioxidant capacity of plasma. The SL did not protect against cardiac lipid peroxydation and did not improve oxidative stress biomarkers. Ex vivo, antiproliferative effects of sera coming from the previous animal experiment were studied on a prostate cancer cell line expressing the androgen receptor (PC3AR). For that, the cells were incubated 48 hours with the rats' sera at 10% instead of foetal bovine serum. Our results showed that sera of SRT and SYT induced over-expression of connexin43 (Cx43), a protein that is down regulated in cancer. Up-regulation can restore cell-to-cell communication and thereby can inhibit cellular growth. The effect of serum of SL was not significant although lycopene intracellular concentration was similar after 48 hours of treatment with sera of SRT and SL. However, because of the small concentrations given with 10% of sera, none of the sera exhibited significant antiproliferative effects. An attempt of identifying metabolites generated in animal urines after SRT, SYT and SL was led by using mass spectrometry. Urinary metabolome of animals was similatly modified after SRT and SYT, and independently from a presence of oxidative stress. Tomato supplementation improved some metabolites previously characterised as biomarkers of oxidative stress. The SL had a different impact on urinary metabolome and did not have beneficial effects. In conclusion, tomato containing or not lycopene can have antioxidant and antiproliferative effects. In this study lycopene effects are null against oxidative and less relevant than those of SRT and SYT in Cx43 up-regulation. The hypothesis is that tomato contains other liposoluble or hydrosoluble micronutrients that can act synergistically in order to counteract oxidative stress, and thereby bring greater effects than lycopene alone.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Caspase-2 regulates oncogene-induced senescence

International audienceCellular senescence is activated by numerous cellular insults, in particular those driving cancer formation, resulting in stable proliferation arrest and acquisition of specific features. By self-opposing to oncogenic stimulation, senescence is considered as a failsafe program, allowing, when functional, to inhibit cancers occurrence. Compelling evidences suggest a tumor suppressive activity of caspase-2, eventually independently of its effect on cell death. The original results described here demonstrate that this tumor suppressive activity of caspase-2 is mediated, at least in part, by its pro-senescing activity. Indeed, we have demonstrated in vitro and in vivo that loss of function of caspase-2 allows to escape oncogenic stress induced senescence. These results are discussed in the context of known tumor suppressive activity of caspase-2

The Transcription Coregulator RIP140 Inhibits Cancer Cell Proliferation by Targeting the Pentose Phosphate Pathway

International audienceCancer cells switch their metabolism toward glucose metabolism to sustain their uncontrolled proliferation. Consequently, glycolytic intermediates are diverted into the pentose phosphate pathway (PPP) to produce macromolecules necessary for cell growth. The transcription regulator RIP140 controls glucose metabolism in tumor cells, but its role in cancer-associated reprogramming of cell metabolism remains poorly understood. Here, we show that, in human breast cancer cells and mouse embryonic fibroblasts, RIP140 inhibits the expression of the gene-encoding G6PD, the first enzyme of the PPP. RIP140 deficiency increases G6PD activity as well as the level of NADPH, a reducing cofactor essential for macromolecule synthesis. Moreover, G6PD knock-down inhibits the gain of proliferation observed when RIP140 expression is reduced. Importantly, RIP140-deficient cells are more sensitive to G6PD inhibition in cell proliferation assays and tumor growth experiments. Altogether, this study describes a novel role for RIP140 in regulating G6PD levels, which links its effect on breast cancer cell proliferation to metabolic rewiring

Comparison of lycopene and tomato effects on biomarkers of oxidative stress in vitamin E deficient rats

Publication Inra prise en compte dans l'analyse bibliométrique des publications scientifiques mondiales sur les Fruits, les Légumes et la Pomme de terre. Période 2000-2012. http://prodinra.inra.fr/record/256699International audienceBACKGROUND: Cohort studies suggested that individuals with higher intake of tomatoes and tomato products have a lower risk of degenerative diseases. Lycopene, an antioxidant and antiproliferative carotenoid, has been hypothesized to be responsible for the health benefits of tomatoes. However, studies demonstrated a higher potential of tomatoes compared to lycopene to reduce oxidative stress or carcinogenesis. AIM OF THE STUDY: Our study aimed at distinguishing lycopene effect from that of tomato on oxidative stress, by using yellow tomato, a tomato variety devoid of lycopene. METHODS: Effects of feeding with none (control), 16% freeze-dried yellow tomato (YT), 16% freeze-dried red tomato (RT) or 0.05% lycopene beadlets (LB) were compared in a rat model with mild oxidative stress induced by low vitamin E diet (LVED). Four groups of 10 rats were fed ad libitum for 6 weeks. Physiological parameters such as ingesta, body, spleen and liver weights, cholesterol and triglycerides (TG) levels were assessed. Lycopene and vitamin E concentrations and oxidative stress biomarkers were measured in the plasma and/or liver and/or heart tissue of the rats. RESULTS: RT, YT, and LB had no effect on rats' ingesta, body and spleen weights. RT, YT and LB had no effect on plasma cholesterol concentration. RT decreased TG level compared to control, YT and LB (P < 0.05). Rats fed RT or LB accumulated lycopene in plasma in contrast with rats fed YT. Heart level of thiobarbituric reactive species (TBARS) in rats fed RT or YT was lower than that in the control and the LB fed rats (P < 0.05). Despite similar concentrations of lycopene in plasma and liver, rats fed LB showed a significantly higher heart level of TBARS than rats fed tomatoes. RT increased erythrocyte superoxide dismutase (eSOD) activity compared with LB and nitric oxide (NO) level compared with control and LB. LB decreased ferric reducing ability of plasma (FRAP) level compared with control, RT and LB (P < 0.05). CONCLUSION: Our study showed for the first time that tomatoes, containing or not containing lycopene, have a higher potential than lycopene to attenuate and or to reverse oxidative stress-related parameters in a mild oxidative stress context

Naturally improving the natural cytotoxicity of natural killer (NK) cells

International audienceThe innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients

Naturally improving the natural cytotoxicity of natural killer (NK) cells

International audienceThe innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients

Serum from rats fed red or yellow tomatoes induces Connexin43 expression independently from lycopene in a prostate cancer cell line

International audienceEpidemiologic studies suggested a protective effect of tomatoes against prostate cancer brought by lycopene, a carotenoid conferring the red colour of tomatoes. However, intervention studies on patients have shown that the preventive effect of tomato was more potent than that of lycopene. The aim of this study was to compare the effects of red tomato, yellow tomato (devoid of lycopene) and lycopene on Connexin43 (Cx43) expression, a protein regulating cell growth, on a prostate cancer cell line expressing the androgen receptor. Cells were incubated with serum from rats fed a control diet (CS) or control diet supplemented with red tomato (RTS), yellow tomato (YTS) or lycopene beadlets (LBS). After exposure of the cells to RTS or YTS for 48 h, the expression of Cx43 was significantly increased compared to cells exposed to CS. Whereas LBS effect was not significantly different. The cells incubated with RTS and LBS had similar levels of lycopene, while those incubated with YTS contained no lycopene. These data first show that serum nutritionally enriched with red and yellow tomatoes could up-regulate Cx43 turn-over in PC3AR cells independently from lycopene level. Within the physiological approach used in the present study, it can be concluded that compounds other than lycopene contribute to the preventive effect of tomatoe

The emerging role of the transcriptional coregulator RIP140 in solid tumors

International audienceRIP140 is a transcriptional coregulator (also known as NRIP1) which plays very important physiological roles by finely tuning the activity of a large number of transcription factors. Noticeably, the RIP140 gene has been shown to be involved in the regulation of energy expenditure, in mammary gland development and intestinal homeostasis as well as in behavior and cognition. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. This short review aims to summarize the role of this transcription factor on nuclear estrogen receptors, E2F and Wnt signaling pathways based on recent observations focusing on breast, ovary, liver and colon tumors