Dissertação (mestrado)—Universidade de Brasília, Faculdade de Comunicação, Programa de Pós-Graduação em Comunicação, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-03-08T20:50:51Z No. of bitstreams: 1 2015_LeandrodeBessaOliveira.pdf: 24067673 bytes, checksum: 74f8b038562b76e2adade134b3f8d682 (MD5) / Approved for entry into archive by Guimaraes Jacqueline(jacqueline.guimaraes@bce.unb.br) on 2016-05-11T15:02:03Z (GMT) No. of bitstreams: 1 2015_LeandrodeBessaOliveira.pdf: 24067673 bytes, checksum: 74f8b038562b76e2adade134b3f8d682 (MD5) / Made available in DSpace on 2016-05-11T15:02:03Z (GMT). No. of bitstreams: 1 2015_LeandrodeBessaOliveira.pdf: 24067673 bytes, checksum: 74f8b038562b76e2adade134b3f8d682 (MD5) / A dissertação delineia o imaginário da putaria através de imagens da história da arte: pinturas, esculturas e artefatos; e imagens midiáticas: fotografias, cartazes e filmes. Tais imagens são designadas como imagens fantasmas, por tratarem de um momento histórico diferente do nosso embora sobreviventes ao tempo. Nesse sentido, tem-se como objetivo traçar uma narrativa dos vestígios imaginários da putaria por meio de uma genealogia da forma e uma etimologia cultural da puta. Procedimento adotado pelo historiador da arte Aby Warburg, o qual nos fornece as ferramentas de análise e interpretação da imagem: analógico, comparativo, por aproximação e filológico. Ideia agitada de Warburg nomeada por Warburg de Pathosformel, ou fórmulas expressivas do páthos. Procuramos compreender também, por esse viés, as relações entre corpo e mito, sagrado e sexual, feitiço e sedução, interdito e transgressão, gozo e consumo, razão e sensibilidade. Assim, as imagens analisadas, predominantemente femininas e portadoras de uma sexualidade livre que nos auxiliaram encontrar, por meio de uma potência criativa e poética, uma estética puta que potencialmente nos permite propor uma filosofia puta que problematize as resistências, os não ditos, o rejeitado e a abjeção. / The dissertation outlines the imaginary of bitching through art historical images: paintings, sculptures and artifacts; and media images such as photographs, posters and movies. Such images are called phantom images for addressing a historical moment different from ours; however it survived through times. In this sense, it has aimed to draw a narrative of imaginary traces of bitching through a genealogy of shape and a cultural etymology of a bitch. The procedure adopted by the art historian Aby Warburg, which provides us with the tools of analysis and interpretation of image: analog, comparative approach and philological. Notion named by Warburg Pathosformel, or the expressive formulas of páthos. We have also tried to understand, from this point of view, the relationship between body and myth, sacred and sexual, witchery and seduction, interdict and transgression, enjoyment and consumption, reason and sensibility. Thus, the analyzed images, predominantly feminine about women with free sexuality, allowed us to find, through a creative and poetic power, a bitch aesthetic rising from a bitch philosophy that discusses the resistance, unspeakable, rejected and abjection. / La dissertation décrit l'imaginaire de la pute à travers des images d’histoire de l’art: peintures, sculptures et objets; et les images des médias: photographies, affiches et films. Ces images sont appelées des images fantômes pour adresser un moment historique différente du nôtre, bien que les survivants au temps. En ce sens, il a pour but tracer une narrative des vestiges imaginaires de la pute à travers d’une généalogie de la forme et d’une étymologie culturelle de la pute. Processus adoptée par l'historien d'art Aby Warburg, qui nous fournit les outils d'analyse et d'interprétation de l'image: analogique, par approche, comparative et philologique. Idée trépidant nommé par Warburg de Pathosformel, ou forme superlative de l’expression des passions (páthos). Essayez de comprendre également, sous cet angle, la relation entre corps et mythe, sacré et sexuelle, sorcellerie et séduction, l’interdit et la transgression, jouissance et consommation, raison et sensibilité. Ainsi, les images analysées, en majorité féminin et des femmes ayant dune sexualité libre, nous ont permis de trouver, grâce à une puissance créatrice et poétique, une esthétique pute résultant d'une philosophie pute qui traite de la résistance, l’indicible, le rejetable et l'abjection.

Under normal conditions, non-transformed cells rely on glycolysis followed by oxidative phosphorylation to generate ATPs. When oxygen is scarce or when cells are actively proliferating, cellular ATPs come mainly from glycolysis. Pyruvate is converted into lactate to allow glycolysis to continue. Interestingly, cancer cells have adapted to favor lactate production even at normal oxygen tensions, exhibiting a metabolic shift known as the Warburg effect. However, the metabolic state of other cellular constituents within the tumor remains mostly unknown. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells. They aid tumor growth and metastasis by providing growth factors, cytokine, ECM remodeling proteins and interacting with other tumor stromal cells. Here I show that the Warburg effect also operates in stromal fibroblasts of the tumor microenvironment. Using mass spectrometry, genetic mouse models, gene expression and methylation studies, I demonstrate that CAFs from human and mouse mammary tumors exhibit hyperactive glycolysis and a metabolic shift towards lactate production. Furthermore, this phenotype may be sustained through epigenetic modifications of endogenous hypoxia-inducible factor 1α, key regulatory enzymes fructose-bisphosphatase 1 and pyruvate kinase M2. Depletion of stromal fibroblasts or suppression of lactate production specifically in these cells alters the metabolic profile of not only the tumors but also the cancer cells and results in impeded tumor growth. These results collectively suggest that tumor growth is dependent on metabolic state and metabolic support of stromal fibroblasts, highlighting these cells as attractive therapeutic targets in controlling cancer progression.

Ovarian cancer is known as the "silent killer," due to its late diagnosis and frequent recurrence after initial treatment.  Finding a new way to diagnose and treat ovarian cancer in conjunction with current therapies is paramount.  By capitalizing on metabolic changes that occur during cancer progression, interventions can be developed.  The Nobel laureate Otto Warburg is credited with discovering an altered metabolic state within cancer cells known as the Warburg effect.  In the Warburg effect, cancer cells participate in an increased rate of aerobic glycolysis with an excess secretion of lactate, allowing for carbon flux into biosynthetic pathways.  Exactly which metabolic pathways are altered in ovarian cancer and at which stage in the progression of ovarian cancer they are occurring was unknown.  Therefore using the recently established mouse ovarian surface epithelial (MOSE) progression model, we were able to measure metabolic changes in varying states of disease and levels of aggressiveness.  As cells progressed from a benign early stage (MOSE-E), through a transitional intermediate stage (MOSE-I), to an aggressive late stage (MOSE-L), the MOSE cells became more glycolytic and lipogenic, establishing the MOSE model as a valuable model for studying ovarian cancer metabolism.  Treating the MOSE cells with the naturally occurring chemotherapeutic agent sphingosine decreased p-AKT  protein levels in the cell, decreased the glycolytic rate and decreased de novo cholesterol synthesis.  Cancer stem cells are known to be resistant to chemotherapy treatments and targeting their metabolism may be promising for combinatorial treatments.  Therefore, the metabolism of highly aggressive tumor-initiating cells (TIC), harvested from ascites of C57Bl/6 mice injected with MOSE-L cells were characterized.  Although the basal metabolism of the TICs was similar to the MOSE-L cells, TICs were more resistant to cell death as a consequence of external stresses and substrate depletion.  The TICs could also up-regulate oxygen consumption rate (OCR) when uncoupled and increase glycolysis when ATP Synthase was inhibited, highlighting their resiliency.  Taken together, we have identified targets for treatment strategies that could suppress the growth of primary tumors and may be effective against TICs, thereby suppressing tumor recurrence and possibly prolonging the life of women with ovarian cancer. / Ph. D.

La presente tesis doctoral busca explicar el funcionamiento de un fenómeno particular, colocando el objeto de estudio en un sistema específico, y a la vez trata de ubicar la noción de investigación al interior de la producción artística contemporánea. Planteado de esta manera, el trabajo tiene una doble función. Por un lado, investigar de manera teórico-práctica la expansión de la imagen, explicando por qué el objeto de estudio (imagen expandida), al ponerse en funcionamiento, crea un fenómeno particular (parpadeo) que es aprehensible en términos de constelación. Por otro, ensayar una aproximación al tema de estudio, que a través de la investigación pueda ser una propuesta artística en sí misma. Es decir, queremos mostrar no sólo las reflexiones en torno al tema de estudio escogido, sino también resaltar la necesidad de afinar el concepto de investigación vinculado a la producción artística. El tratamiento teórico-práctico del tema de estudio, resulta en una puesta en evidencia de las particularidades que la investigación puede asumir al interior de la práctica artística como tal, y muestra cómo artistas y teóricos pueden llegar a conclusiones similares, por caminos diversos, pero siempre a partir de su propia producción. / Suter Latour, G. (2010). ANÁLISIS TEÓRICO-PRÁCTICO DEL VACÍO Y DEL SILENCIO EN LA PRODUCCIÓN ARTÍSTICA CONTEMPORÁNEA [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/14977

Background: Tumor cells are highly dependent on glucose even in the presence of oxygen. This concept called the Warburg effect is a hallmark of cancer and strategies are considered to therapeutically exploit the phenomenon such as ketogenic diets. The success of such strategies is dependent on a profound understanding of tumor cell metabolism. With new techniques it is now possible to thoroughly analyze the metabolic responses to the withdrawal of substrates and their substitution by others. In the present study we used gas chromatography coupled to mass spectrometry (GC-MS) to analyze how glioblastoma brain tumor cells respond metabolically when glucose is withdrawn and substituted by pyruvate. Methods: Glioblastoma brain tumor cells were cultivated in medium with high (25 mM), medium (11 mM) or low (5.5 mM) glucose concentration or with pyruvate (5 mM). After 24 h GC-MS metabolite profiling was performed. Results: The abundances of most metabolites were dependent on the supply of glucose in tendency but not in a linear manner indicating saturation at high glucose. Noteworthy, a high level of sorbitol production and release was observed at high concentrations of glucose and high release of alanine, aspartate and citrate were observed when glucose was substituted by pyruvate. Intermediates of the TCA cycle were present under all nutritional conditions and evidence was found that cells may perform gluconeogenesis from pyruvate. Conclusions: Our experiments reveal a high plasticity of glioblastoma cells to changes in nutritional supply which has to be taken into account in clinical trials in which specific diets are considered for therapy.

Malgré le manque d’études sur ce sujet, le cancer est considéré comme une des principales causes d’hyperlactatémie de type B chez le chien. Les cellules malignes ont une production accrue de lactates secondaire à une glycolyse aérobie accrue, via l’effet Warburg. Les mécanismes ne sont pas encore clairement établis mais certains auteurs suggèrent que le cancer pourrait causer une hyperlactatémie via l’effet Warburg. Cette étude a pour objectif de déterminer si les tumeurs malignes peuvent être associées à une hyperlactatémie cliniquement significative (≥2,5 mmol/L) chez le chien. Trente-sept chiens atteints de tumeurs malignes ont été recrutés (22 atteints de tumeurs hématopoïétiques et 15 de tumeurs non hématopoïétiques). Le diagnostic était confirmé par analyse histologique, ou cytologique en cas de lymphome. Les autres causes possibles d’hyperlactatémie étaient écartées puis la mesure des lactates sanguins était réalisée sur sang veineux jugulaire immédiatement analysé avec le LactatePro®. Aucun chien n’était hyperlactatémique. La concentration moyenne en lactates sanguins était de 1,09 mmol/L. La concentration moyenne en lactates sanguins pour les chiens atteints de tumeurs non hématopoïétiques et hématopoïétiques était respectivement de 0,95 mmol/L et de 1,19 mmol/L. Les chiens atteints de lymphome (n=18) avaient une concentration moyenne en lactates sanguins de 1,15 mmol/L. Les tumeurs malignes ne sont pas associées à une hyperlactatémie de type B cliniquement significative chez le chien. L’hyperlactatémie tumorale est donc une complication rare chez le chien. Son diagnostic devrait conduire à une investigation minutieuse des autres causes d’hyperlactatémie. / Cancer is considered a cause of type B hyperlactatemia in dogs. However, studies evaluating cancer as a cause of clinically relevant type B hyperlactatemia (≥2.5 mmol/L) are lacking. It is well accepted that cancer cells have a higher lactate production due to increased aerobic glycolysis, known as the Warburg effect. The mechanisms through which aerobic glycolysis occurs are not well elucidated but it has been suggested that neoplasia may cause type B hyperlactatemia via this process. The aim of this study is to determine if canine malignant tumors could be associated with a clinically relevant type B hyperlactatemia (≥ 2.5 mmol/L). Thirty-seven dogs with malignant tumors were included: 22 with hematopoietic and 15 with solid tumors. Histology was used to confirm the diagnosis (cytology was considered appropriate for lymphoma). Confounding factors associated with hyperlactatemia were excluded. Lactate measurements were obtained from a free flow jugular whole blood sample and immediately analyzed using the LactatePro®. All dogs had lactate values less than 2.5 mmol/L. The mean blood lactate concentration was 1.09 mmol/L. The mean blood lactate concentration for solid and hematopoietic tumor was 0.95 mmol/L and 1.19 mmol/L respectively. Dogs with lymphoma (n = 18) had a mean blood lactate concentration of 1.15 mmol/L. Malignant tumors were not considered a cause of clinically relevant type B hyperlactatemia. Therefore, cancer related type B hyperlactatemia in dogs with cancer is uncommon and its diagnosis should prompt careful investigation for causes other than cancer.

Dans la plupart des pays industrialisés, le cancer du sein est la principale cause de décès chez les femmes. Le microenvironnement tumoral (TME) joue un rôle important dans la progression du cancer du sein. Le TME est un tissu complexe composé d’une matrice extracellulaire remaniée, de fibroblastes, de cellules inflammatoires et endothéliales. Récemment un nouveau composant cellulaire du TMA a été identifié. Il est formé par des adipocytes modifiés situés en regard de cellules cancéreuses appelées "adipocytes associés au cancer" (CAA). Ces constituants ajoutent à la complexité du TME. La protéase matricielle Matrix Metalloproteinase-11 (MMP-11) est une protéine du TME, elle est sécrétée par les «fibroblastes associés au cancer» (CAF) au centre de la tumeur et par les CAA à la périphérie de la tumeur (le front d’invasion). Soutenant l'idée que la MMP11 contribue à la progression tumorale, des études antérieures ont montré qu’une expression élevée était associée à une survie sans récidive plus courte des patientes atteintes d'un cancer du sein. Cependant, le mécanisme d'action spécifique de cette protéase est resté mal compris. Des études plus récentes ont montré que la MMP-11 est un régulateur négatif du développement du tissu adipeux et qu’elle module le métabolisme énergétique. Ces observations suggéraient que l'expression de MMP-11 dans le TME pourrait participer directement à la progression de la tumeur en modulant le métabolisme du tissu adipeux au profit des cellules cancéreuses. Cependant, la façon dont la MMP-11 agit, notamment à l'interface entre les cellules cancéreuses du sein et les CAAs, reste largement inconnue. Pour l’étudier, nous avons développé des modèles précliniques de cancer de la glande mammaire chez la souris par génie génétique. Tout d'abord, des souris déficientes (perte de fonction-LOF) ou surexprimant MMP-11 (Gain de Fonction-GOF) ont été croisées avec un modèle génétique de tumeurs mammaires (MMTV-PyMT). Des résultats cohérents ont été obtenus en utilisant les deux modèles. La MMP11 favorise la progression tumorale précoce, en augmentant la prolifération et en réduisant l'apoptose des cellules cancéreuses. De plus, l’expression de la MMP-11 a été associée à un changement métabolique dans la tumeur et à une altération significative de l’Unfolded Protein Response mitochondriale (UPRmt) et à une activation du stress du réticulum endoplasmique (UPRER). Ces données confortent l'idée selon laquelle la MMP-11 contribue à une réponse métabolique adaptative favorisant la croissance du cancer. Deuxièmement, pour aborder directement la fonction de la MMP-11 produite par le tissu adipeux sur la progression du cancer, nous avons généré une lignée de souris transgénique (appelée aP2-MMP11-IRES-GFP) dans laquelle l'expression de MMP-11 est contrôlée par un promoteur spécifique du tissu adipeux. L’implantation directe de cellules cancéreuses syngéniques dans le coussinet mammaire de ces souris a montré que l'expression de la MMP11 favorisait la croissance tumorale. Finalement, nos données soutiennent le concept selon lequel l'expression de MMP-11 par les adipocytes associés au cancer (CAA) contribuerait à une réponse métabolique adaptative favorisant la croissance du cancer. Ils renforcent aussi l’intérêt que représente la MMP-11 comme cible pour le traitement du cancer. / Breast cancer is the most common leading cause of death in women. The tumor microenvironment (TME) plays an important role in breast cancer progression. The TME is a complex tissue composed of extracellular matrix proteins, fibroblasts, inflammatory and endothelial cells. Recently modified adipocytes called “Cancer-Associated Adipocytes” (CAAs) were identified as emerging components of the TME adding into the complexity of this tumor component. Matrix Metalloproteinase-11 (MMP-11) is a protein from the TME, it is secreted by "Cancer-Associated Fibroblasts" (CAFs) in the center of the tumor and by CAAs in the tumor periphery also qualified as the “invasive front”. Previous studies showed that elevated MMP11 expression is associated with a poorer outcome in breast cancer patients supporting the idea that MMP11 contributes to tumor progression but the mechanism of action remained unclear. Recent studies showed that MMP-11 is a negative regulator of adipose tissue development and controls energy metabolism. These observations suggested that MMP-11 expression in the TME may directly participate in breast tumor progression by modulating the adipose tissue metabolism at the benefit of cancer cells. However, how MMP-11 acts in the TME notably at the interface of breast cancer cells and CAAs remains largely unknown. To study the role of MMP-11 on breast cancer progression, we developed a series of preclinical mouse mammary gland tumour models by genetic engineering. First, mice either deficient- (Loss of Function-LOF) or overexpressing- MMP-11 were crossed with a genetic model of spontaneous mammary tumors (MMTV-PyMT). Consistent results were obtained using GOF and LOF, showing that MMP11 favored early tumor progression, by increasing proliferation and reducing apoptosis of cancer cells. Of interest, MMP-11 was associated with a metabolic switch in the tumor and the activation of the mitochondrial unfolded protein response (UPRmt) and endoplasmic reticulum stress (UPRER). These data support the idea that MMP-11 contributes to an adaptive metabolic response favoring cancer growth. Second, to directly address the function of MMP-11 produced by the adipose tissue on cancer progression, we generated a transgenic mouse line (named aP2-MMP11-IRES-GFP) in which MMP-11 expression is controlled by an adipose tissue-specific promoter. Direct grafting of syngeneic cancer cells in the mammary fad-pad of these mice showed that MMP11 expression favored tumor growth. Altogether our data support the idea that MMP-11 expression by cancer associated adipocytes contributes to an adaptive metabolic response, named metabolic flexibility, favoring cancer growth. They further substantiate the potential of MMP-11 as a target for cancer therapy.

Malgré le manque d’études sur ce sujet, le cancer est considéré comme une des principales causes d’hyperlactatémie de type B chez le chien. Les cellules malignes ont une production accrue de lactates secondaire à une glycolyse aérobie accrue, via l’effet Warburg. Les mécanismes ne sont pas encore clairement établis mais certains auteurs suggèrent que le cancer pourrait causer une hyperlactatémie via l’effet Warburg. Cette étude a pour objectif de déterminer si les tumeurs malignes peuvent être associées à une hyperlactatémie cliniquement significative (≥2,5 mmol/L) chez le chien. Trente-sept chiens atteints de tumeurs malignes ont été recrutés (22 atteints de tumeurs hématopoïétiques et 15 de tumeurs non hématopoïétiques). Le diagnostic était confirmé par analyse histologique, ou cytologique en cas de lymphome. Les autres causes possibles d’hyperlactatémie étaient écartées puis la mesure des lactates sanguins était réalisée sur sang veineux jugulaire immédiatement analysé avec le LactatePro®. Aucun chien n’était hyperlactatémique. La concentration moyenne en lactates sanguins était de 1,09 mmol/L. La concentration moyenne en lactates sanguins pour les chiens atteints de tumeurs non hématopoïétiques et hématopoïétiques était respectivement de 0,95 mmol/L et de 1,19 mmol/L. Les chiens atteints de lymphome (n=18) avaient une concentration moyenne en lactates sanguins de 1,15 mmol/L. Les tumeurs malignes ne sont pas associées à une hyperlactatémie de type B cliniquement significative chez le chien. L’hyperlactatémie tumorale est donc une complication rare chez le chien. Son diagnostic devrait conduire à une investigation minutieuse des autres causes d’hyperlactatémie. / Cancer is considered a cause of type B hyperlactatemia in dogs. However, studies evaluating cancer as a cause of clinically relevant type B hyperlactatemia (≥2.5 mmol/L) are lacking. It is well accepted that cancer cells have a higher lactate production due to increased aerobic glycolysis, known as the Warburg effect. The mechanisms through which aerobic glycolysis occurs are not well elucidated but it has been suggested that neoplasia may cause type B hyperlactatemia via this process. The aim of this study is to determine if canine malignant tumors could be associated with a clinically relevant type B hyperlactatemia (≥ 2.5 mmol/L). Thirty-seven dogs with malignant tumors were included: 22 with hematopoietic and 15 with solid tumors. Histology was used to confirm the diagnosis (cytology was considered appropriate for lymphoma). Confounding factors associated with hyperlactatemia were excluded. Lactate measurements were obtained from a free flow jugular whole blood sample and immediately analyzed using the LactatePro®. All dogs had lactate values less than 2.5 mmol/L. The mean blood lactate concentration was 1.09 mmol/L. The mean blood lactate concentration for solid and hematopoietic tumor was 0.95 mmol/L and 1.19 mmol/L respectively. Dogs with lymphoma (n = 18) had a mean blood lactate concentration of 1.15 mmol/L. Malignant tumors were not considered a cause of clinically relevant type B hyperlactatemia. Therefore, cancer related type B hyperlactatemia in dogs with cancer is uncommon and its diagnosis should prompt careful investigation for causes other than cancer.

Le catabolisme exacerbé du glucose et de la glutamine est actuellement reconnu comme une caractéristique des cellules cancéreuses, qui leur procure un avantage prolifératif via la production et l’accumulation de plusieurs métabolites au niveau du microenvironnement. Parmi ces métabolites, l’acide lactique représente une molécule de signalisation clé, favorisant la migration et les métastases. Mon projet de thèse s’inscrit dans le contexte d’une étude du métabolisme glycolytique associé aux cellules tumorales à division rapide. Durant ce projet, nous nous sommes intéressés à la caractérisation génétique et fonctionnelle des transporteurs MCT (MonoCarboxylate Transporters) 1 et 4, qui sont des symporteurs H+/lactate dont l’expression membranaire et la fonctionnalité requièrent la liaison avec une protéine chaperonne : CD147/BASIGINE (BSG). Afin de mieux explorer la physiologie des complexes MCT/BSG, et valider le ciblage de l’export d’acide lactique comme une nouvelle approche anti-cancer, nous avons développé une stratégie visant à invalider le gène BSG et/ou MCT4, en utilisant la technologie des Zinc Finger Nucleases (ZFN), dans des lignées cellulaires cancéreuses humaines de côlon, poumon et glioblastome. D’abord, nous avons démontré, que l’effet pro-tumoral majeur de BSG est lié à son action directe sur la stabilisation des MCTs au niveau des tumeurs glycolytiques et non pas à la production des metalloprotéases. Ensuite, nous avons démontré pour la première fois que l’inhibition concomitante de MCT1 et MCT4 est nécessaire pour induire une baisse significative de la tumorigénécité in vivo. / Enhanced glucose and glutamine catabolism has become a recognized feature of cancer cells, leading to accumulation of metabolites in the tumour microenvironment, which offers growth advantages to tumours. Among these metabolites is emerging as a key signalling molecule that plays a pivotal role in cancer cell migration and metastasis. In this thesis, we focused on the genetic and functional characterization of monocarboxylate transporters (MCT) 1 and 4, which are H+/lactate symporters that require an interaction with an ancillary protein, CD147/BASIGIN (BSG), for their plasma membrane expression and function. To further explore the physiology of MCT/BSG complexes and validate the blockade of lactic acid export as an anti-cancer strategy, we designed experiments using Zinc Finger Nuclease mediated BSG and/or MCT4 gene knockouts in human colon adenocarcinoma, lung carcinoma and glioblastoma cell lines. First of all, we demonstrated that the major protumoural action of BSG is to control the energetics of glycolytic tumours via MCT1/4 activity and not to produce matrix metalloproteases. Second, we showed for the first time that combined inhibition of both MCT1 and MCT4 transporters is required to achieve a significant reduction in the tumour growth in vivo. Moreover, our findings reported that disruption of the BSG gene dramatically reduced the plasma membrane expression and lactate transport activity of both MCT1 and MCT4, leading to increased accumulation of intracellular pools of lactic and pyruvic acids, decreased intracellular pH and reduced rate of glycolysis.

L’être humain est exposé quotidiennement et simultanément à des dizaines de polluants environnementaux, pourtant il n’existe encore que peu ou pas d’études sur les effets de ces mélanges. Des études épidémiologiques et transcriptomiques montrent que les polluants peuvent perturber le métabolisme glucidique et lipidique. Le lien entre métabolisme et cancer a été démontré depuis plusieurs décennies, en effet, une dérégulation du métabolisme oxydatif, appelée effet Warburg, et commune à presque toutes les cellules tumorales se caractérise par une déviation du métabolisme oxydatif mitochondrial vers une glycolyse anaérobie entrainant une augmentation de la production de lactate. Pour ce travail les effets d’un mélange de deux polluants organiques persistants ayant des voies de signalisation différentes sont étudiés. Le mélange associe la TCDD, une substance cancérigène, à un pesticide l’α-endosulfan, afin d’évaluer les effets combinés de ces deux polluants sur le métabolisme énergétique de cellules cancéreuses coliques humaines Caco2. Le traitement des cellules pendant 48 heures par la TCDD (25 nM) et l’α-endosulfan (10µM) conduit à une diminution de l’oxydation du glucose, corrélée à une augmentation de la production de lactate, alors que chaque polluant seul exerce un effet peu significatif. Le mélange diminue l’activité globale de la mitochondrie caractérisée par une diminution de la respiration cellulaire, et de la production d’ATP sans toutefois modifier l’intégrité mitochondriale. L’étude des mécanismes impliqués dans ces effets indique l’implication de l’AMPK et du complexe PDH, deux enzymes clés régulant de façon très importante la glycolyse cellulaire ; en effet l’inhibition de l’AMPK abolit les effets des polluants. Des modifications du calcium intracellulaire qui régule entre autre l’activité de ces deux enzymes sont observées et l’inhibition du calcium abolit également les effets des polluants. Ces travaux montrent que le mélange induit une aggravation de la dérégulation du phénotype métabolique des cellules Caco2 à l’état prolifératif. Cela pourrait signifier une synergie de l’activité de ces polluants qui pourrait accentuer ce phénotype dans un contexte tumorale via un mécanisme impliquant le calcium. / During tumorigenesis most of cancer cells exhibit an altered metabolism that is characterized by an elevated uptake of glucose and an increased glycolytic rate; this phenomenon is known as the Warburg effect. Compelling recent evidences suggest that alteration of cellular metabolism is critical during cancer development and constitutes a major feature of aggressive tumour. Considering the recent observations on the impact of persistent organic pollutants (POPs) on cell metabolism, we hypothesize that POPs could exert their carcinogenic effects by promoting metabolic alterations that could converge to a metabolic shift supporting a tumoral phenotype. Proliferating colon cancer cells (Caco2) were treated with TCDD (25 nM) or/and α-endosulfan (10 µM), two environmental pollutants mainly produced by human activities and designated by the International Agency for Research on Cancer as probably or well-established carcinogenic to humans. A significant decrease of glucose and glutamine oxidation (60%) was observed after a treatment for 48 hours with the two pollutants while each pollutant alone had no significant effect. These observations are correlated with an increased lactate production by two fold. These effects are maintained in the presence of antioxidative NAC (10 mM), suggesting that they are independent of the oxidative status of the cell. We also observed a decreased incorporation of glucose in total lipids (50%). The ATP production and the cell respiration level were significantly decreased by the mixture by about 50% and 80%, respectively. In the same conditions, the glycogen production and the NADPH/NADPH,H+ ratio were unchanged. Taken together, these results suggest that POPs could worsen the metabolic phenotype of cancer cells. The molecular mechanisms underlying the POPs-induced metabolic reprograming are under investigation and should provide a better understanding of the signalling pathways involved in POPs action on the regulation of the energetic metabolism balance and their consequence on cancer.