7 research outputs found

    Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion

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    At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications

    Selenium nanoparticles trigger alterations in ovarian cancer cell biomechanics

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    High dose selenium acts as a cytotoxic agent, with potential applications in cancer treatment. However, clinical trials have failed to show any chemotherapeutic value of selenium at safe and tolerated doses (<90 ÎĽg/day). To enable the successful exploitation of selenium for cancer treatment, we evaluated inorganic selenium nanoparticles (SeNP), and found them effective in inhibiting ovarian cancer cell growth. In both SKOV-3 and OVCAR-3 ovarian cancer cell types SeNP treatment resulted in significant cytotoxicity. The two cell types displayed contrasting nanomechanical responses to SeNPs, with decreased surface roughness and membrane stiffness, characteristics of OVCAR-3 cell death. In SKOV-3, cell membrane surface roughness and stiffness increased, both properties associated with decreased metastatic potential. The beneficial effects of SeNPs on ovarian cancer cell death appear cell type dependent, and due to their low in vivo toxicity offer an exciting opportunity for future cancer treatment

    Proteolysis inhibition by hibernating bear serum leads to increased protein content in human muscle cells

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    Muscle atrophy is one of the main characteristics of human ageing and physical inactivity, with resulting adverse health outcomes. To date, there are still no efficient therapeutic strategies for its prevention and/or treatment. However, during hibernation, bears exhibit a unique ability for preserving muscle in conditions where muscle atrophy would be expected in humans. Therefore, our objective was to determine whether there are components of bear serum which can control protein balance in human muscles. In this study, we exposed cultured human differentiated muscle cells to bear serum collected during winter and summer periods, and measured the impact on cell protein content and turnover. In addition, we explored the signalling pathways that control rates of protein synthesis and degradation. We show that the protein turnover of human myotubes is reduced when incubated with winter bear serum, with a dramatic inhibition of proteolysis involving both proteasomal and lysosomal systems, and resulting in an increase in muscle cell protein content. By modulating intracellular signalling pathways and inducing a protein sparing phenotype in human muscle cells, winter bear serum therefore holds potential for developing new tools to fight human muscle atrophy and related metabolic disorders

    Bio-géochimie du cancer : Utilisation des nanoparticules de sélénium dans le traitement et des isotopes du cuivre dans la détection des cancers ovariens

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    Ovarian cancer is the seventh most common cancer in women with five-year survival rates of less than 45%, and only 20% of cases are detected at early stages of the disease. Major challenges still exist to treat this lethal disease.The development of new drugs that target better cancer cells and reduce side effects is highly needed. Selenium at high doses has been shown to act as a cytotoxic agent, with potential applications in cancer treatment. However, clinical trials have failed to show any chemotherapeutic value of selenium at safe and tolerated doses (<90 g/day). To enable the successful exploitation of selenium for cancer treatment, I evaluated inorganic selenium nanoparticles (SeNP), and found them effective in inhibiting ovarian cancer cell growth. In both SKOV-3 and OVCAR-3 ovarian cancer cell lines SeNP treatment resulted in significant cytotoxicity. The two cell types displayed contrasting nanomechanical responses to SeNPs, with decreased surface roughness and membrane stiffness characteristic of OVCAR-3 cell responses. In SKOV-3, cell membrane surface roughness and stiffness increased, both are properties associated with decreased metastatic potential. Very excitingly I made the novel discovery that SeNPs dramatically increase histone methylation at three histone marks, namely H3K4, H3K27 and H3K9. This effect was partially blocked by pharmacological agents that blocked histone methyltransferase (HMT) function. Gene expression profiling of SeNP treated cells demonstrated that Se caused changes in the expression of HMTs suggesting one mechanism for its ability to alter histone methylation. Further interrogation of RNA seq data showed the SeNPs impact on the expression of genes linked to hallmarks of cancer such as DNA repair activation, ROS response, extracellular matrix organization. The beneficial effects of SeNPs on ovarian cancer cell death appear to be cell type dependent, and due to their low in vivo toxicity, offer an exciting opportunity for future cancer treatment.Finally, following on from recent studies in breast and colorectal cancer patients revealing that measurement of circulating copper isotopes (63Cu/65Cu ratio) can be related to cancer development I investigated this in clinical ovarian cancer samples (blood and tissue). A significant decrease in copper isotopic ratios in the serum of cancer donors was observed demonstrating the potential effectiveness of 63Cu/65Cu for the blood-based detection of ovarian cancer.Le cancer des ovaires est le septième cancer le plus commun chez les femmes dont le taux de survie à 5 ans est en deçà de 45% et dont le taux de détection des premiers stades de développement est inférieur à 20%. Avant d’arriver à un traitement, de nombreux défis restent à relever.Le développement de nouveaux traitements ciblant spécifiquement les cellules cancéreuses en réduisant les effets secondaires liés au traitement est nécessaire. Pour cela, le Sélénium a été étudié et a démontré à forte doses d’être efficace contre les cellules cancéreuses in vitro. De plus, les essais cliniques ont montré que l’utilisation de doses tolérables de sélénium (<90µg/jour) n’avait pas d’effet thérapeutique contre le cancer. Le développement de nouvelles formes de sélénium afin d’augmenter les doses administrées est donc nécessaire afin d’atteindre l’effet thérapeutique souhaité. Au cours de cette thèse j’ai mesuré l’effet de formes agrégées de sélénium appelées nanoparticules et démontré leur capacité à inhiber la croissance de cellules cancéreuses ovariennes. Dans les lignées cellulaires cancéreuses ovariennes SKOV-3 et OVCAR-3, le traitement aux SeNPs a déclenché la mort cellulaire. La mesure des propriétés nanomécaniques de ces deux lignées cellulaires après traitement a démontré un effet différent des SeNPs en fonction du type cellulaire. Les cellules OVCAR-3 ont vu diminuer leur rugosité de surface ainsi que leur rigidité cellulaire alors que les cellules SKOV-3 ont augmenté leur rigidité et leur rugosité, ces deux caractéristiques étant liées à une diminution de leur potentiel métastatique. De plus, le traitement aux SeNPs a augmenté de manière considérable la méthylation de trois lysines de l’histone 3 H3K4, H3K27 et H3K9. Cette méthylation a pu être bloquée par l’utilisation d’inhibiteurs de méthyltransférases spécifiques de ces marqueurs. L’étude du profil d’expression des deux lignées cellulaires après traitement a démontré le fait que le sélénium induit des modifications d’expression des méthyltransférases nous permettant de suggérer un mécanisme d’action du sélénium. De plus les SeNPs ont démontré leur impact sur l’expression marqueurs cancéreux comme l’activation de la réparation de l’ADN, la réponse aux espèces réactives de l’oxygène, la réorganisation de la matrice extracellulaire. L’effet des SeNPs semble dépendant du type cellulaire cependant leur bonne tolérabilité in vivo offre de bonnes perspectives d’utilisation en tant que traitement du cancer.Enfin, dans la continuité de récentes études sur le cancer du sein le cancer colorectal s’intéressant à la mesure des isotopes du cuivre (rapport 63Cu/65Cu) et démontrant leur potentiel dans la détection du développement de ces cancers, j’ai pu mesurer le contenu isotopique de biopsies et de prélèvements sanguins issus de patientes atteintes de cancers ovariens. J’ai pu mesurer une diminution significative du rapport des isotopes du cuivre dans le sérum des patientes cancéreuses en comparaison avec des témoins sains démontrant l’efficacité de détection des cancers par la mesure des isotopes du cuivre dans le sang

    Bio-Geochemistry of ovarian cancer : Role of selenium nanoparticles in treatment and copper isotopes in detection of ovarian cancer.

    No full text
    Le cancer des ovaires est le septième cancer le plus commun chez les femmes dont le taux de survie à 5 ans est en deçà de 45% et dont le taux de détection des premiers stades de développement est inférieur à 20%. Avant d’arriver à un traitement, de nombreux défis restent à relever.Le développement de nouveaux traitements ciblant spécifiquement les cellules cancéreuses en réduisant les effets secondaires liés au traitement est nécessaire. Pour cela, le Sélénium a été étudié et a démontré à forte doses d’être efficace contre les cellules cancéreuses in vitro. De plus, les essais cliniques ont montré que l’utilisation de doses tolérables de sélénium (<90µg/jour) n’avait pas d’effet thérapeutique contre le cancer. Le développement de nouvelles formes de sélénium afin d’augmenter les doses administrées est donc nécessaire afin d’atteindre l’effet thérapeutique souhaité. Au cours de cette thèse j’ai mesuré l’effet de formes agrégées de sélénium appelées nanoparticules et démontré leur capacité à inhiber la croissance de cellules cancéreuses ovariennes. Dans les lignées cellulaires cancéreuses ovariennes SKOV-3 et OVCAR-3, le traitement aux SeNPs a déclenché la mort cellulaire. La mesure des propriétés nanomécaniques de ces deux lignées cellulaires après traitement a démontré un effet différent des SeNPs en fonction du type cellulaire. Les cellules OVCAR-3 ont vu diminuer leur rugosité de surface ainsi que leur rigidité cellulaire alors que les cellules SKOV-3 ont augmenté leur rigidité et leur rugosité, ces deux caractéristiques étant liées à une diminution de leur potentiel métastatique. De plus, le traitement aux SeNPs a augmenté de manière considérable la méthylation de trois lysines de l’histone 3 H3K4, H3K27 et H3K9. Cette méthylation a pu être bloquée par l’utilisation d’inhibiteurs de méthyltransférases spécifiques de ces marqueurs. L’étude du profil d’expression des deux lignées cellulaires après traitement a démontré le fait que le sélénium induit des modifications d’expression des méthyltransférases nous permettant de suggérer un mécanisme d’action du sélénium. De plus les SeNPs ont démontré leur impact sur l’expression marqueurs cancéreux comme l’activation de la réparation de l’ADN, la réponse aux espèces réactives de l’oxygène, la réorganisation de la matrice extracellulaire. L’effet des SeNPs semble dépendant du type cellulaire cependant leur bonne tolérabilité in vivo offre de bonnes perspectives d’utilisation en tant que traitement du cancer.Enfin, dans la continuité de récentes études sur le cancer du sein le cancer colorectal s’intéressant à la mesure des isotopes du cuivre (rapport 63Cu/65Cu) et démontrant leur potentiel dans la détection du développement de ces cancers, j’ai pu mesurer le contenu isotopique de biopsies et de prélèvements sanguins issus de patientes atteintes de cancers ovariens. J’ai pu mesurer une diminution significative du rapport des isotopes du cuivre dans le sérum des patientes cancéreuses en comparaison avec des témoins sains démontrant l’efficacité de détection des cancers par la mesure des isotopes du cuivre dans le sang.Ovarian cancer is the seventh most common cancer in women with five-year survival rates of less than 45%, and only 20% of cases are detected at early stages of the disease. Major challenges still exist to treat this lethal disease.The development of new drugs that target better cancer cells and reduce side effects is highly needed. Selenium at high doses has been shown to act as a cytotoxic agent, with potential applications in cancer treatment. However, clinical trials have failed to show any chemotherapeutic value of selenium at safe and tolerated doses (<90 g/day). To enable the successful exploitation of selenium for cancer treatment, I evaluated inorganic selenium nanoparticles (SeNP), and found them effective in inhibiting ovarian cancer cell growth. In both SKOV-3 and OVCAR-3 ovarian cancer cell lines SeNP treatment resulted in significant cytotoxicity. The two cell types displayed contrasting nanomechanical responses to SeNPs, with decreased surface roughness and membrane stiffness characteristic of OVCAR-3 cell responses. In SKOV-3, cell membrane surface roughness and stiffness increased, both are properties associated with decreased metastatic potential. Very excitingly I made the novel discovery that SeNPs dramatically increase histone methylation at three histone marks, namely H3K4, H3K27 and H3K9. This effect was partially blocked by pharmacological agents that blocked histone methyltransferase (HMT) function. Gene expression profiling of SeNP treated cells demonstrated that Se caused changes in the expression of HMTs suggesting one mechanism for its ability to alter histone methylation. Further interrogation of RNA seq data showed the SeNPs impact on the expression of genes linked to hallmarks of cancer such as DNA repair activation, ROS response, extracellular matrix organization. The beneficial effects of SeNPs on ovarian cancer cell death appear to be cell type dependent, and due to their low in vivo toxicity, offer an exciting opportunity for future cancer treatment.Finally, following on from recent studies in breast and colorectal cancer patients revealing that measurement of circulating copper isotopes (63Cu/65Cu ratio) can be related to cancer development I investigated this in clinical ovarian cancer samples (blood and tissue). A significant decrease in copper isotopic ratios in the serum of cancer donors was observed demonstrating the potential effectiveness of 63Cu/65Cu for the blood-based detection of ovarian cancer

    Selenium Deficiency—From Soil to Thyroid Cancer

    No full text
    Selenium (Se) is an essential micronutrient present in human diet, entering in the composition of selenoproteins as selenocysteine (Se-Cys) amino acid. At the thyroid level, these proteins play an important role as antioxidant and in hormone metabolism. Selenoproteins are essential for the balance of redox homeostasis and antioxidant defense of mammalian organisms, while the corresponding imbalance is now recognized as the cause of many diseases including cancer. The food chain is the main source of Se in human body. Dietary intake is strongly correlated with Se content in soil and varies according to several factors such as geology and atmospheric input. Both Se deficiency and toxicity have been associated with adverse health effects. This review synthesizes recent data on the transfer of Se from soil to humans, Se U-shaped deficiency and toxicity uptake effects and particularly the impact of Se deficiency on thyroid cancer

    Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion

    No full text
    At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications
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