Cytosolic serine hydroxymethyltransferase controls lung adenocarcinoma cells migratory ability by modulating AMP kinase activity

Nutrient utilization and reshaping of metabolism in cancer cells is a well-known driver of malignant transformation. Less clear is the influence of the local microenvironment on metastasis formation and choice of the final organ to invade. Here we show that the level of the amino acid serine in the cytosol affects the migratory properties of lung adenocarcinoma (LUAD) cells. Inhibition of serine or glycine uptake from the extracellular milieu, as well as knockdown of the cytosolic one-carbon metabolism enzyme serine hydroxymethyltransferase (SHMT1), abolishes migration. Using rescue experiments with a brain extracellular extract, and direct measurements, we demonstrate that cytosolic serine starvation controls cell movement by increasing reactive oxygen species formation and decreasing ATP levels, thereby promoting activation of the AMP sensor kinase (AMPK) by phosphorylation. Activation of AMPK induces remodeling of the cytoskeleton and finally controls cell motility. These results highlight that cytosolic serine metabolism plays a key role in controlling motility, suggesting that cells are able to dynamically exploit the compartmentalization of this metabolism to adapt their metabolic needs to different cell functions (movement vs. proliferation). We propose a model to explain the relevance of serine/glycine metabolism in the preferential colonization of the brain by LUAD cells and suggest that the inhibition of serine/glycine uptake and/or cytosolic SHMT1 might represent a successful strategy to limit the formation of brain metastasis from primary tumors, a major cause of death in these patients

The emerging role of amino acids of the brain microenvironment in the process of metastasis formation

Brain metastases are the most severe clinical manifestation of aggressive tumors. Melanoma, breast, and lung cancers are the types that prefer the brain as a site of metastasis formation, even if the reasons for this phenomenon still remain to be clarified. One of the main characteristics that makes a cancer cell able to form metastases in the brain is the ability to interact with the endothelial cells of the microvasculature, cross the blood–brain barrier, and metabolically adapt to the nutrients available in the new microenvironment. In this review, we analyzed what makes the brain a suitable site for the development of metastases and how this microenvironment, through the continuous release of neurotransmitters and amino acids in the extracellular milieu, is able to support the metabolic needs of metastasizing cells. We also suggested a possible role for amino acids released by the brain through the endothelial cells of the blood–brain barrier into the bloodstream in triggering the process of extravasation/invasion of the brain parenchyma

Participatory monitoring of river flows.

Water users in northwestern Tunisia, like the Medjerda watershed, are increasingly withdrawing water from hydro-systems. This is a response to the effects of climate change that are causing strong variability. These water withdrawals result in an increase in the state of stress over time (Fehri et al., 2020). The involvement of citizens, in a participatory manner, is likely to help raise awareness among water users. The use of Mobile application has been validated in the region of Medjez El Bab by the involvement of different citizen groups (Fehri et al., 2020a; Fehri, 2021). The objective of this sheet is to capitalize on these achievements and to be used in the north-west of Tunisia for monitoring droughts or floods

Anticancer Activity of (S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((pyridin-4-ylmethyl)amino)propan-2-yl)-1H-indole-2-carboxamide (RS4690), a New Dishevelled 1 Inhibitor

: Wingless/integrase-11 (WNT)/β-catenin pathway is a crucial upstream regulator of a huge array of cellular functions. Its dysregulation is correlated to neoplastic cellular transition and cancer proliferation. Members of the Dishevelled (DVL) family of proteins play an important role in the transduction of WNT signaling by contacting its cognate receptor, Frizzled, via a shared PDZ domain. Thus, negative modulators of DVL1 are able to impair the binding to Frizzled receptors, turning off the aberrant activation of the WNT pathway and leading to anti-cancer activity. Through structure-based virtual screening studies, we identified racemic compound RS4690 (1), which showed a promising selective DVL1 binding inhibition with an EC50 of 0.74 ± 0.08 μM. Molecular dynamic simulations suggested a different binding mode for the enantiomers. In the in vitro assays, enantiomer (S)-1 showed better inhibition of DVL1 with an EC50 of 0.49 ± 0.11 μM compared to the (R)-enantiomer. Compound (S)-1 inhibited the growth of HCT116 cells expressing wild-type APC with an EC50 of 7.1 ± 0.6 μM and caused a high level of ROS production. These results highlight (S)-1 as a lead compound for the development of new therapeutic agents against WNT-dependent colon cancer

The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism

Enzymes of intermediary metabolism are often reported to have moonlighting functions as RNA-binding proteins and have regulatory roles beyond their primary activities. Human serine hydroxymethyltransferase (SHMT) is essential for the one-carbon metabolism, which sustains growth and proliferation in normal and tumour cells. Here, we characterize the RNA-binding function of cytosolic SHMT (SHMT1) in vitro and using cancer cell models. We show that SHMT1 controls the expression of its mitochondrial counterpart (SHMT2) by binding to the 5'untranslated region of the SHMT2 transcript (UTR2). Importantly, binding to RNA is modulated by metabolites in vitro and the formation of the SHMT1-UTR2 complex inhibits the serine cleavage activity of the SHMT1, without affecting the reverse reaction. Transfection of UTR2 in cancer cells controls SHMT1 activity and reduces cell viability. We propose a novel mechanism of SHMT regulation, which interconnects RNA and metabolites levels to control the cross-talk between cytosolic and mitochondrial compartments of serine metabolism.Associazione Italiana per la Ricerca sul Cancro [AIRC-IG2015 n. 16720 to F.C., AIRC-MFAG2017 n. 20447 to A.P.); Sapienza University of Rome [RM11715C646D693E to S.R.; RP11715C644A5CCE, GA116154C8A94E3D to F.C.]; Istituto-Pasteur Italia-Fondazione Cenci Bolognetti [Grant 2015 to F.C.]; European Research Council [RIBOMYLOME_309545 to G.G.T.]; Spanish Ministry of Economy and Competitiveness [BFU2014-55054-P, BFU2017-86970-P]; ‘Fundació La Marató de TV3’ [PI043296]; Ministerio de Ciencia e Innovación (Plan Nacional de I+D+I, Spain) [SAF2016-80639-P to J.A.M.]. Funding for open access charge: Associazione Italiana per la Ricerca sul Cancro [AIRC-IG2015 n. 16720

Differential inhibitory effect of a pyrazolopyran compound on human serine hydroxymethyltransferase-amino acid complexes

Serine hydroxymethyltransferase (SHMT) is a pivotal enzyme in one-carbon metabolism that catalyses the reversible conversion of serine and tetrahydrofolate into glycine and methylenetetrahydrofolate. It exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. Research on one-carbon metabolism in cancer cell lines has shown that SHMT1 preferentially catalyses serine synthesis, whereas in mitochondria SHMT2 is involved in serine breakdown. Recent research has focused on the identification of inhibitors that bind at the folate pocket. We have previously found that a representative derivative of the pyrazolopyran scaffold, namely 2.12, inhibits both SHMT isoforms, with a preference for SHMT1, causing apoptosis in lung cancer cell lines. Here we show that the affinity of 2.12 for SHMT depends on the identity of the amino acid substrate bound to the enzyme. The dissociation constant of 2.12 is 50-fold lower when it binds to SHMT1 enzyme-serine complex, as compared to the enzyme-glycine complex. Evidence is presented for a similar behaviour of compound 2.12 in the cellular environment. These findings suggest that the presence and identity of the amino acid substrate should be considered when designing SHMT inhibitors. Moreover, our data provide the proof-of-concept that SHMT inhibitors selectively targeting the directionality of one-carbon metabolism flux could be designed

Varia 2010

Pour bénéficier de l'envoi par courriel des avis de mise en ligne ainsi que des informations diverses collectées par "Informations - Géographie Physique", veuillez vous inscrire à la lettre de Physio-Géo (en bas et à gauche de la page d'accueil ou par courriel : [email protected]). Les personnes inscrites à la lettre de Physio-Géo qui n'ont pas accès aux fichiers pdf par l'intermédiaire de leur organisme, peuvent les obtenir gracieusement auprès de la revue ([email protected]). Quarante et un articles ont été reçus en 2010. Onze articles ont été mis en ligne (1 soumis en 2008, 5 soumis en 2009 et 5 soumis en 2010). Pour les articles reçus et/ou mis en ligne sont intervenus comme réviseurs : Mohammed Achite (Maroc), Frédéric Alexandre, Djamal Al Karkouri (Maroc), Mparany Andriamihamina (Madagascar), Julien Andrieu, Valérie Andrieu-Ponel, Pierre-Alain Ayral, Moulay Belkhodja (Algérie), Khéloufi Benabdeli (Algérie), Federico Boenzi (Italie), Christophe Bouvier, Nathalie Carcaud, El Amine Cherif (Algérie), Anne-Laure Cognard-Plancq, Jeannine Corbonnois, Dov Corenblit, Claude Cosandey, Adeline Cotonnec, Nicole de Courcel de Garambé, Christophe Cudennec, Yvette Dewolf, Bernard Dumont, Yahia El Khalki (Maroc), Christophe Esposito, Cyril Fleurant, Pierre Freytet, Nourredine Gaaloul (Tunisie), François Gazelle, Emmanuel Gille, Pierre Guérémy, Dominique Harmand, Hamadi Hbaieb (Tunisie), Frédéric Hoffmann, Raouf Karray (Tunisie), Jean-Pierre Laborde, Abdellah Laouina (Maroc), René Lhénaff, Jacques Lepart, Patrick Louis, Brice Martin, Mohamed Meddi (Algérie), Khalladi Mederbal (Algérie), Michel Mietton, Vincent Ollivier, André Ozer, Marie-Josée Penven, Philippe Ponel, Christian Puech, Simone Ratsivalaka (Madagascar), Jean Riser, Éric Roose, Henri Rougier, Jean-Noël Salomon, Laurent Schmitt, Dominique Sellier, Georges Serpantié, Yacine Spiga (Algérie), Pierre Usselmann, Marie-Claude Valaison, Emmanuelle Vaudour. Les révisions des articles publiés en 2010 ont été coordonnées par les membres du comité de direction : Claude Martin, Jean-Louis Ballais, Aïcha Benmohammadi, Marianne Cohen, Georges De Noni, Bertrand Lemartinel et Alain Marre. Ultimes corrections et composition des textes : Claude Martin