Search

Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG-mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth.

Summary: The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC. : Bellier et al. demonstrate that MGO stress is a constant feature of KRAS-mutated CRC tumors. MGO induces a key survival pathway implicated in resistance to EGFR-targeted therapy in CRC. The scavenging of this oncometabolite could be beneficial in the treatment of both wild-type and mutant KRAS CRC tumors. Keywords: methylglyoxal, colorectal cancer, KRAS mutation, EGFR-targeted therapy, Hsp27, carnosine, aminoguanidine, cetuximab, AKT signaling

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.

Metabolic syndrome and type 2 diabetes are associated with increased risk of breast cancer development and progression. Methylglyoxal (MG), a glycolysis by-product, is generated through a non-enzymatic reaction from triose-phosphate intermediates. This dicarbonyl compound is highly reactive and contributes to the accumulation of advanced glycation end products. In this study, we analyzed the accumulation of Arg-pyrimidine, a MG-arginine adduct, in human breast adenocarcinoma and we observed a consistent increase of Arg-pyrimidine in cancer cells when compared with the non-tumoral counterpart. Further immunohistochemical comparative analysis of breast cancer subtypes revealed that triple negative lesions exhibited low accumulation of Arg-pyrimidine compared with other subtypes. Interestingly, the activity of glyoxalase 1 (Glo-1), an enzyme that detoxifies MG, was significantly higher in triple negative than in other subtype lesions, suggesting that these aggressive tumors are able to develop an efficient response against dicarbonyl stress. Using breast cancer cell lines, we substantiated these clinical observations by showing that, in contrast to triple positive, triple negative cells induced Glo-1 expression and activity in response to MG treatment. This is the first report that Arg-pyrimidine adduct accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes.

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to D-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression., SCOPUS: ar.j, info:eu-repo/semantics/published

Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment. DOI: http://dx.doi.org/10.7554/eLife.19375.001

Introduction Methylglyoxal (MG) is spontaneously produced during glycolysis. MG reacts with proteins, lipids and DNA, thus inducing a dicarbonyl stress. Glyoxalase 1 (GLO1) detoxifies MG into D-Lactate. High MG is notably associated with diabetes and cancer as the latter presents a deregulated energy metabolism where tumour cells use glycolysis rather than mitochondrial respiration. The impact of MG on cancer is ambiguous as some studies reported an anti-tumour and others a pro-tumour effect upon GLO1 silencing. Material and methods In this study, we aimed to evaluate the effect of MG stress on a panel of cancer cell lines: MDA-MB-231 known to be glycolytic and MCF7 cells known to be more oxidative breast cancer cells and U87-MG and U251 glioblastoma cell lines. We characterised glycolysis, MG production and detoxification under different conditions in these cell lines. U87-MG tumour growth upon MG treatment was evaluated using the chick chorioallantoic membrane tumour model (CAM). Results and discussions We observed that only MDA-MB-231 and U87-MG cell lines are able to increase their glycolysis flux upon glucose stimulation. In these conditions, both cell lines increased their MG production and detoxification via the glyoxalase system. Under exogenous MG treatment, both glycolytic cell lines showed increased expression of both NRF2 and its target gene GLO1, whereas no ROS accumulation was detected. Upon GLO1 activity inhibition, an alternative MG detoxification system, the aldo-keto reductase (AKR) enzymes, is significantly increased at least in U87-MG cells. Finally, U87-MG cells xenografted on CAM and treated with MG showed an increased growth at low MG doses while high doses reduced tumour growth. Both effects could be reversed by co-treatment with a potent MG-scavenger, L-Carnosine. Conclusion Our data demonstrate for the first time that cancer cells are not equal when facing MG stress. Their response to MG is mainly dependent upon energy metabolism and detoxification capacity (including GLO1 and AKRs). Reduced glutathione level is also an important feature to consider. Ongoing studies will help identify the molecular mecanisms underlying MG dual effect in cancer.

Introduction Methylglyoxal (MG) is an endogenous dicarbonyl spontaneously produced during glycolysis able to react with proteins, lipids and DNA, inducing a carbonyl stress. Glyoxalase 1 (GLO1) detoxifies MG into D-Lactate. High MG is notably associated with diabetes and cancer. Melanoma is the most deadly form of skin cancer. Therapy is notably based on the inhibition of the MAPK pathway, often over activated. Unfortunately, BRAF and MEK inhibitors are briefly efficient as tumours rapidly develop resistance mechanisms. Melanoma tumours are generally highly glycolytic and therefore inevitably produce high amounts of MG, accumulating Advanced Glycation End products (AGEs). Phenformin, a metformin analogue with MG-scavenging properties, improves the therapeutic effect of BRAF inhibition. This observation is in good accordance with our hypothesis that MG could be involved in progression and resistance of melanoma. Material and methods This study aims to assess the metabolic profile of various human melanoma cell lines comprising BRAF and/or MEK inhibitors sensitive and resistant cells. First, we plan to explore thoroughly dicarbonyl stress status in these cell lines and in patient tissues. Next, we will subject melanoma cells to anti-carbonyl stress agents such as l-carnosine and aminoguanidine alone or in combination with MAPK pathway inhibitors and assess their effect on tumour cell survival. Results and discussions IHC staining of argpyrimidines, MG-derived AGEs, in a collection of melanoma samples showed that MG carbonyl stress is a constant feature in melanoma. MG AGEs were detectable in both BRAF inhibitors sensitive and resistant cell lines: A375 and A2058, respectively. Interestingly, the treatment of these cells with exogenous MG induced different responses: A375 cells increased their MG detoxification system and their metabolic activity as assessed by their increased GLUT1 and GLUT3 glucose transporters and PGC1alpha mitochondrial regulator. Whereas, A2058 resistant melanoma cells showed a decrease of both GLO1 activity and the metabolic markers investigated. Conclusion Ongoing experiments will help to understand these phenotypes and to further characterise a serie of WT and BRAF mutated melanoma cells. We plan to assess carbonyl stress in a larger human melanoma collection to investigate the correlation with tumour stage, metastasis, overall survival and resistance to therapy. Finally, we will test the efficacy of a combined therapy using BRAF and/or MEK inhibitors and MG scavenger molecules such as carnosine.

Une dimension importante n’est pas prise en compte dans les outils actuels de selection de projets: les interactions entre les projets. Pour completer les typologies qui distinguent l’objet ou le mode de fonctionnement des interactions, nous distinguons six formes d’interactions. Nous pouvons alors etablir le reseau de relations entretenues par les projets et proposer des strategies de gestion selon la forme d’interactions identifiee.

Metabolic disorders influence breast cancer development and progression. Methylglyoxal (MGX), is a highly reactive glycolytic byproduct able to inflict carbonyl stress to proteins, lipids and DNA. The possible role of MGX in breast cancer development has not been yet extensively explored. We analyzed the accumulation of Arg-pyrimidine adducts, in a series of more than 100 human breast adenocarcinoma and we observed a consistent increased of MGX adducts in cancer cells compared to the non-tumoral counterpart. Most triple negative lesions examined exhibited low accumulation of Arg-pyrimidine residues compared other subtypes. Intriguingly, the level of expression of glyoxalase 1 (Glo-1), an enzyme that detoxifies MGX, was similar in both triple negative and other subtype lesions, suggesting a potential difference in the Glo-1 activity. This hypothesis is supported by our preliminary results on breast cancer cell lines, showing that triple negative cells are more efficient to respond to treatment with MGX by ...

This work investigates managerial dynamics of customer participation and its evolution in financial context. We are interested in managerial dynamics because most of the studies related in co-production is about consumers and the current literature on co-production lacks empirical investigations in financial services. Despite its increasing popularity in the last decade co-production is not a new phenomenon. Customer participation has existed since a very long period of time especially in services marketing and is still evolving in different industries. The following definitions have been adopted for this research. Customer participation has been defined as "the degree to which the customer is involved in producing and delivering the service" (Dabholkar 1990, p. 484). Lengnick–Hall et al (2000) define co-production as “engaging customers as active participants in the organization’s work”. A comprehensive analysis of marketing literature about co-production and consumer participation issues leads us to four different approaches: a services marketing approach focusing on largely customer participation, a managerial approach that puts the customer at the center of co-creation process, an innovative approach where the customer actively takes part in innovation, a critical approach focusing on working consumer concept. The central question for the research is “How and why do banks engage their customers in co-production? Four constructs have been selected in order to answer this question: motives, processes problems and outcomes. Five European banks have been selected for the study. A detailed multiple case study analysis revealed three different community types: market research communities, Innovation communities, Cooperation communities. Another contribution is about the evolution of these communities in time. Some communities (ING and Cetelem) evolved according to needs and priorities of financial institutions. The analysis of these banks shows that three important dynamics feed building and managing a community in financial context: customer centricity, managerial support and the need for innovation. In addition, these three different community types have different processes. Problems of community management in financial industry are also investigated in detail in order to better answer “how” question. Besides financial, technical and organizational problems, the most important problem seems to be the management of open and harsh criticisms. The second important problem is the efficient community management in financial industry. In addition, internal dynamics, complexity and intangibility of financial services and resistance to change may also complicate effective community management. According to our findings, motives of financial institutions are not much different from motives of other companies. Research, innovation and co-production of new products and services are most common motives. However motives of open communities were different, they were more business related. Main motive for open communities was cost-cutting, besides cost-cutting, increasing consumers’ loyalty, having a closer contact with clients, engaging them and assigning the community new tasks are also important motives. According to our findings, there are also common and different outcomes for these three different communities. As stated several times by Von Hippel (2006) and Kozinets (1999) online communities are efficient mechanisms for marketing research. Our findings also supported their results. Besides, communities are also important in increasing brand awareness (Seraj 2012), visibility and better internal communication and cooperation (Ramasvamy and Gouillart 2010), know-how sharing and breaking down the barriers between different departments.; Ce travail comprend une analyse détaillée des pratiques managériales des communautés virtuelles dans le secteur banquier. Nous nous sommes intéressés aux dynamiques managériales de la co-production parce que la plupart des études liées à la coproduction concernent les produits et les consommateurs. De plus, la littérature actuelle sur la coproduction manque des investigations empiriques dans les services financiers. Nous avons commencé par proposer des définitions pour pouvoir comprendre et analyser les concepts que nous mobilisons. La participation des clients a été définie comme la mesure dans laquelle le client est impliqué dans la production et le dévouement du service (Dabholkar, 1990). La coproduction est également définie comme engageant les clients en tant que participants actifs dans le travail de l'organisation (Lengnick Hall et al, 2000). Nous avons identifié quatre courants importants qui expliquent chronologiquement la participation du consommateur au développement de nouveaux produits/services: Marketing des services, l’approche managériale, la participation basée sur l’innovation, l’approche qui critique la participation du consommateur. La question de recherche centrale est "Comment et pourquoi les banques engagent-elles leurs clients dans un processus de co-production?" Nous avons identifié quatre dimensions au début de la recherche pour pouvoir comprendre les dynamiques managériales. Les dimensions étaient l’objectif, le processus, les résultats et les problèmes de la participation du consommateur. Nous avons décidé d’étudier cinq différentes institutions financières Européennes. Nous avons réalisé une conception de recherche des études de cas multiples afin de répondre à cette question dans un contexte financier. Nous avons identifié différents types de communautés chacune ayant des fonctions et des objectifs différents : communautés de recherche, communautés d'innovation, communauté de coopération ouverte avec des activités. Ces trois types de communauté ont des processus différents. La deuxième découverte est liée à l'évolution de ces communautés avec le temps. Certaines communautés (ING et Cetelem) ont évolué; Nous voyons une transformation de ces communautés selon les besoins et les priorités des institutions financières. Quant aux caractéristiques de ces institutions, processus et problèmes, l'analyse de ces banques montre que trois dynamiques importantes alimentent la construction et la gestion d'une communauté dans un contexte financier: client-centricité, soutien managérial et besoin d'innovation. D’après nos observations, le problème principal porte sur la gestion de la communauté. Il est difficile de gérer une communauté ouverte où n'importe qui peut venir et publier des idées et des critiques négatives. Les problèmes techniques, bureaucratiques et budgétaires existent aussi. La recherche, l'innovation et la coproduction de nouveaux produits et services sont les motifs les plus courants. Cependant, les motivations des communautés ouvertes étaient plus liées aux affaires. Le principal motif d'ouverture des communautés était la réduction des coûts, outre la réduction des coûts, l'augmentation de la fidélité des consommateurs, le contact plus étroit avec les clients, leur engagement et l'attribution de nouvelles tâches à la communauté. Comme indiqué plusieurs fois par Von Hippel (2006) et Kozinets (1999), les communautés en ligne sont des mécanismes efficaces pour l’étude du marché. En plus, les communautés sont également importantes pour accroitre la notoriété de la marque (Seraj 2012), la visibilité et la meilleure communication interne et la coopération (Ramasvamy et Gouillart 2010), le partage du savoir-faire et l'élimination des barrières entre les différents départements.

This work investigates managerial dynamics of customer participation and its evolution in financial context. We are interested in managerial dynamics because most of the studies related in co-production is about consumers and the current literature on co-production lacks empirical investigations in financial services. Despite its increasing popularity in the last decade co-production is not a new phenomenon. Customer participation has existed since a very long period of time especially in services marketing and is still evolving in different industries. The following definitions have been adopted for this research. Customer participation has been defined as "the degree to which the customer is involved in producing and delivering the service" (Dabholkar 1990, p. 484). Lengnick–Hall et al (2000) define co-production as “engaging customers as active participants in the organization’s work”. A comprehensive analysis of marketing literature about co-production and consumer participation issues leads us to four different approaches: a services marketing approach focusing on largely customer participation, a managerial approach that puts the customer at the center of co-creation process, an innovative approach where the customer actively takes part in innovation, a critical approach focusing on working consumer concept. The central question for the research is “How and why do banks engage their customers in co-production? Four constructs have been selected in order to answer this question: motives, processes problems and outcomes. Five European banks have been selected for the study. A detailed multiple case study analysis revealed three different community types: market research communities, Innovation communities, Cooperation communities. Another contribution is about the evolution of these communities in time. Some communities (ING and Cetelem) evolved according to needs and priorities of financial institutions. The analysis of these banks shows that three important dynamics feed building and managing a community in financial context: customer centricity, managerial support and the need for innovation. In addition, these three different community types have different processes. Problems of community management in financial industry are also investigated in detail in order to better answer “how” question. Besides financial, technical and organizational problems, the most important problem seems to be the management of open and harsh criticisms. The second important problem is the efficient community management in financial industry. In addition, internal dynamics, complexity and intangibility of financial services and resistance to change may also complicate effective community management. According to our findings, motives of financial institutions are not much different from motives of other companies. Research, innovation and co-production of new products and services are most common motives. However motives of open communities were different, they were more business related. Main motive for open communities was cost-cutting, besides cost-cutting, increasing consumers’ loyalty, having a closer contact with clients, engaging them and assigning the community new tasks are also important motives. According to our findings, there are also common and different outcomes for these three different communities. As stated several times by Von Hippel (2006) and Kozinets (1999) online communities are efficient mechanisms for marketing research. Our findings also supported their results. Besides, communities are also important in increasing brand awareness (Seraj 2012), visibility and better internal communication and cooperation (Ramasvamy and Gouillart 2010), know-how sharing and breaking down the barriers between different departments.; Ce travail comprend une analyse détaillée des pratiques managériales des communautés virtuelles dans le secteur banquier. Nous nous sommes intéressés aux dynamiques managériales de la co-production parce que la plupart des études liées à la coproduction concernent les produits et les consommateurs. De plus, la littérature actuelle sur la coproduction manque des investigations empiriques dans les services financiers. Nous avons commencé par proposer des définitions pour pouvoir comprendre et analyser les concepts que nous mobilisons. La participation des clients a été définie comme la mesure dans laquelle le client est impliqué dans la production et le dévouement du service (Dabholkar, 1990). La coproduction est également définie comme engageant les clients en tant que participants actifs dans le travail de l'organisation (Lengnick Hall et al, 2000). Nous avons identifié quatre courants importants qui expliquent chronologiquement la participation du consommateur au développement de nouveaux produits/services: Marketing des services, l’approche managériale, la participation basée sur l’innovation, l’approche qui critique la participation du consommateur. La question de recherche centrale est "Comment et pourquoi les banques engagent-elles leurs clients dans un processus de co-production?" Nous avons identifié quatre dimensions au début de la recherche pour pouvoir comprendre les dynamiques managériales. Les dimensions étaient l’objectif, le processus, les résultats et les problèmes de la participation du consommateur. Nous avons décidé d’étudier cinq différentes institutions financières Européennes. Nous avons réalisé une conception de recherche des études de cas multiples afin de répondre à cette question dans un contexte financier. Nous avons identifié différents types de communautés chacune ayant des fonctions et des objectifs différents : communautés de recherche, communautés d'innovation, communauté de coopération ouverte avec des activités. Ces trois types de communauté ont des processus différents. La deuxième découverte est liée à l'évolution de ces communautés avec le temps. Certaines communautés (ING et Cetelem) ont évolué; Nous voyons une transformation de ces communautés selon les besoins et les priorités des institutions financières. Quant aux caractéristiques de ces institutions, processus et problèmes, l'analyse de ces banques montre que trois dynamiques importantes alimentent la construction et la gestion d'une communauté dans un contexte financier: client-centricité, soutien managérial et besoin d'innovation. D’après nos observations, le problème principal porte sur la gestion de la communauté. Il est difficile de gérer une communauté ouverte où n'importe qui peut venir et publier des idées et des critiques négatives. Les problèmes techniques, bureaucratiques et budgétaires existent aussi. La recherche, l'innovation et la coproduction de nouveaux produits et services sont les motifs les plus courants. Cependant, les motivations des communautés ouvertes étaient plus liées aux affaires. Le principal motif d'ouverture des communautés était la réduction des coûts, outre la réduction des coûts, l'augmentation de la fidélité des consommateurs, le contact plus étroit avec les clients, leur engagement et l'attribution de nouvelles tâches à la communauté. Comme indiqué plusieurs fois par Von Hippel (2006) et Kozinets (1999), les communautés en ligne sont des mécanismes efficaces pour l’étude du marché. En plus, les communautés sont également importantes pour accroitre la notoriété de la marque (Seraj 2012), la visibilité et la meilleure communication interne et la coopération (Ramasvamy et Gouillart 2010), le partage du savoir-faire et l'élimination des barrières entre les différents départements.