References of "Castronovo, Vincenzo"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailMyoferlin contributes to the metastatic phenotype of pancreatic cancer cells by enhancing their migratory capacity through the control of oxidative phosphorylation
Rademaker, Gilles ULiege; Costanza, Brunella; Anania, Sandy ULiege et al

in Cancers (in press)

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with an overall survival of 5%, and is the second cause of death by cancer, mainly linked to its high metastatic aggressiveness ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with an overall survival of 5%, and is the second cause of death by cancer, mainly linked to its high metastatic aggressiveness. Accordingly, understanding the mechanisms sustaining the PDAC metastatic phenotype remains a priority. In this study, we have generated and used a murine in vivo model to select clones from the human PANC-1 PDAC cell line that exhibit a high propensity to seed and metastasized into the liver. We showed that myoferlin, a protein previously reported to be overexpressed in PDAC, is significantly involved in the migratory abilities of the selected cells. We first report that highly PANC-1 metastatic clones expressed significantly higher myoferlin level than the corresponding low metastatic ones. Using scratch wound and Boyden’s chamber assays, we show that cells expressing high myoferlin level have higher migratory potential than cells characterized by a low myoferlin abundance. Moreover, we demonstrate that myoferlin silencing leads to a migration decrease associated to a reduction of mitochondrial respiration. Since mitochondrial oxidative phosphorylation has been shown to be implicated in the tumor progression and dissemination, our data identify myoferlin as a valid potential therapeutic target in PDAC. [less ▲]

Detailed reference viewed: 19 (3 ULiège)
Full Text
Peer Reviewed
See detailTGFBI, an ECM interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration
Costanza, Brunella; Rademaker, Gilles ULiege; Tiamiou, Assia ULiege et al

in International Journal of Cancer (2019)

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC ... [more ▼]

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high TGFBI expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates FAK signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic ECM interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies. [less ▲]

Detailed reference viewed: 49 (16 ULiège)
Full Text
Peer Reviewed
See detailHuman colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis.
Rademaker, Gilles ULiege; Costanza, Brunella; Bellier, Justine ULiege et al

in Oncogenesis (2019)

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use ... [more ▼]

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use of glycolysis to produce energy. Recent studies demonstrated that mitochondrial electron transport chain inhibitor reduced colon cancer tumour growth. Accumulating evidence show that myoferlin, a member of the ferlin family, is highly expressed in several cancer types, where it acts as a tumour-promoter and participates in the metabolic rewiring towards oxidative metabolism. In this study, we showed that myoferlin expression in colon cancer lesions is associated with low patient survival and is higher than in non-tumoural adjacent tissue. Human colon cancer cells silenced for myoferlin exhibit a reduced oxidative phosphorylation activity associated with mitochondrial fission leading, ROS accumulation, decreased cell growth, and increased apoptosis. We observed the triggering of a DNA damage response culminating to a cell cycle arrest in wild-type p53 cells. The use of a p53 null cell line or a compound able to restore p53 activity (Prima-1) reverted the effects induced by myoferlin silencing, confirming the involvement of p53. The recent identification of a compound interacting with a myoferlin C2 domain and bearing anti-cancer potency identifies, together with our demonstration, this protein as a suitable new therapeutic target in colon cancer. [less ▲]

Detailed reference viewed: 84 (28 ULiège)
Full Text
Peer Reviewed
See detailMethylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer
Nokin, Marie-Julie ULiege; Bellier, Justine ULiege; Durieux, Florence et al

in Breast Cancer Research (2019), 21(1

Detailed reference viewed: 58 (14 ULiège)
Full Text
Peer Reviewed
See detailHuman peroxidasin 1 promotes angiogenesis through ERK1/2, Akt and FAK pathways
Medfai, Hayfa; Khalil, Alia; Rousseau, Alexandre et al

in Cardiovascular Research (2019), 115(2)

The term angiogenesis refers to sprouting of new blood vessels from pre-existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and ... [more ▼]

The term angiogenesis refers to sprouting of new blood vessels from pre-existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and the extracellular ma- trix. Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase found embedded in the basement mem- branes. As it promotes the stabilization of extracellular matrix, we investigated its possible role in angiogenesis both in vitro and in vivo. We analysed the effects of peroxidasin 1 gene silencing and supplementation by recombinant hsPxd01 in TeloHAEC endothelial cells on cell migration, tubulogenesis in matrigel, and intracellular signal transduction as assessed by kinase phosphorylation and expression of pro-angiogenic genes as measured by qRT–PCR. We further evaluated the angiogenic potential of recombinant peroxidasin in a chicken chorioallantoic membrane model. RNA silencing of endogenous hsPxd01 significantly reduced tube formation and cell migration, whereas supplementation by the recombinant peroxidase promoted tube formation in vitro and stimulated vascularization in vivo through its catalytic activity. Moreover, recombinant hsPxd01 promoted phosphorylation of Extracellular signal-Regulated Kinases (ERK1/2), Protein kinase B (Akt), and Focal Adhesion Kinase (FAK), and induced the expression of pro- angiogenic downstream genes: Platelet Derived Growth Factor Subunit B (PDGFB), endothelial-derived Heparin Binding EGF-like growth factor (HB-EGF), CXCL-1, Hairy-Related Transcription Factor 1 (HEY-1), DNA-binding protein inhibitor (ID-2), Snail Family Zinc Finger 1 (SNAI-1), as well as endogenous hsPxd01. However, peroxidasin silencing significantly reduced Akt and FAK phosphorylation but induced ERK1/2 activation after supplementation by recombinant hsPxd01. While hsPxd01 silencing significantly reduced expression of HEY-1, ID-2, and PDGFB, it did not affect expression of SNAI-1, HB-EGF, and CXCL-1 after supplementation by recombinant hsPxd01. Our findings suggest a role of enzymatically active peroxidasin 1 as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signalling. [less ▲]

Detailed reference viewed: 42 (9 ULiège)
Full Text
Peer Reviewed
See detailMethylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer
Bellier, Justine ULiege; Nokin, Marie-Julie ULiege; Lardé, Eva ULiege et al

in Diabetes Research and Clinical Practice (2019)

Detailed reference viewed: 43 (9 ULiège)
Full Text
Peer Reviewed
See detailL’analyse des acides gras érythrocytaires maternels en début de grossesse révèle un faible index oméga-3
Hoge, Axelle ULiege; Bernardy, Florence; Donneau, Anne-Françoise ULiege et al

in Nutrition Clinique et Metabolisme (2018, December), 32(4),

Detailed reference viewed: 64 (10 ULiège)
See detailMethylglyoxal-induced cardonyl stress in melanoma progression and response to therapy
Tiamiou, Assia ULiege; Durieux, Florence; Nokin, Marie-Julie et al

Poster (2018, November 26)

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This ... [more ▼]

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This dicarbonyl compound is highly reactive and induces the formation of advanced glycation end-products 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. Aldo-keto reductase enzymes can also detoxify MG to acetol and lactaldehyde. Melanoma, the most deadly form of skin cancer, is associated with BRAF or NRAS mutations. These mutations are characterized by a glycolytic switch thus leading to potential accumulation of MG stress. [less ▲]

Detailed reference viewed: 18 (2 ULiège)
See detailMethylglyoxal-induced cardonyl stress in melanoma progression and response to therapy
Tiamiou, Assia ULiege; Durieux, Florence; Nokin, Marie-Julie et al

Poster (2018, September 28)

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This ... [more ▼]

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This dicarbonyl compound is highly reactive and induces the formation of advanced glycation end-products 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. Aldo-keto reductase enzymes can also detoxify MG to acetol and lactaldehyde. Melanoma, the most deadly form of skin cancer, is associated with BRAF or NRAS mutations. These mutations are characterized by a glycolytic switch thus leading to potential accumulation of MG stress. [less ▲]

Detailed reference viewed: 14 (3 ULiège)
See detailMethylglyoxal-induced cardonyl stress in melanoma progression and response to therapy
Tiamiou, Assia ULiege; Durieux, Florence; Nokin, Marie-Julie et al

Poster (2018, September 13)

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This ... [more ▼]

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This dicarbonyl compound is highly reactive and induces the formation of advanced glycation end-products 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. Aldo-keto reductase enzymes can also detoxify MG to acetol and lactaldehyde. Melanoma, the most deadly form of skin cancer, is associated with BRAF or NRAS mutations. These mutations are characterized by a glycolytic switch thus leading to potential accumulation of MG stress. [less ▲]

Detailed reference viewed: 21 (2 ULiège)
Full Text
See detailMyoferlin controls mitochondrial structure and metabolism in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness.
Rademaker, Gilles ULiege; Hennequière, Vincent; Brohée, Laura et al

Poster (2018, July 01)

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on classical chemotherapies. Cell fraction can survive to the chemotherapy and is responsible for tumor relapse. It appears that these cells rely on oxydative phosphorylation (OXPHOS) for survival. Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer. In the present study, we discovered that myoferlin was more expressed in cell lines undergoing (OXPHOS) than in glycolytic cell lines. In the former cell lines, we showed that myoferlin silencing reduced OXPHOS activity and forced cells to switch to glycolysis. The decrease in OXPHOS activity is associated with mitochondrial condensation and network disorganization. An increase of Dynamin-related protein (DRP)-1 phosphorylation in myoferlin-depleted cells led us to suggest mitochondrial fission, reducing cell proliferation, ATP production and inducing autophagy and ROS accumulation. Electron microscopy observation revealed mitophagy, suggesting mitochondrial alterations. To confirm the clinical importance of myoferlin in PDAC, we showed that low myoferlin expression was significantly correlated to high overall survival. Myoferlin staining of PDAC sections was negatively correlated with several 18FDG PET indices indicating that glycolytic lesions had less myoferlin. These observations are fully in accordance with our in vitro data. As the mitochondrial function was associated with cell chemoresistance, the metabolic switch induced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies. Among them, targeting functional domains (C2, Dysf, …) of myoferlin should be a priority. [less ▲]

Detailed reference viewed: 49 (9 ULiège)
Full Text
Peer Reviewed
See detailPropranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.
Brohée, Laura; Peulen, Olivier ULiege; Nusgens, Betty et al

in Scientific Reports (2018), 8(1), 7050

Propranolol, a widely used non-selective beta-adrenergic receptor blocker, was recently shown to display anticancer properties. Its potential to synergize with certain drugs has been also outlined ... [more ▼]

Propranolol, a widely used non-selective beta-adrenergic receptor blocker, was recently shown to display anticancer properties. Its potential to synergize with certain drugs has been also outlined. However, it is necessary to take into account all the properties of propranolol to select a drug that could be efficiently combined with. Propranolol was reported to block the late phase of autophagy. Hence, we hypothesized that in condition enhancing autophagy flux, cancer cells should be especially sensitive to propranolol. 2DG, a glycolysis inhibitor, is an anti-tumor agent having limited effect in monotherapy notably due to induction of pro-survival autophagy. Here, we report that treatment of cancer cells with propranolol in combination with the glycolysis inhibitor 2DG induced a massive accumulation of autophagosome due to autophagy blockade. The propranolol +2DG treatment efficiently prevents prostate cancer cell proliferation, induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial bioenergetics and aggravates ER stress in vitro and also suppresses tumor growth in vivo. Our study underlines for the first time the interest to take advantage of the ability of propranolol to inhibit autophagy to design new anti-cancer therapies. [less ▲]

Detailed reference viewed: 51 (9 ULiège)
Full Text
Peer Reviewed
See detailMyoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Nokin, Marie-Julie ULiege et al

in Oncogene (2018)

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 105 (39 ULiège)
Full Text
Peer Reviewed
See detailLow omega-3 index values and monounsaturated fatty acid levels in early pregnancy: an analysis of maternal erythrocytes fatty acids
Hoge, Axelle ULiege; Bernardy, Florence; Donneau, Anne-Françoise ULiege et al

in Lipids in Health and Disease (2018), 17

Detailed reference viewed: 54 (13 ULiège)
Full Text
Peer Reviewed
See detailMurine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases
Blomme, A.; van Simaeys, G.; Doumont, G. et al

in Oncogene (2018), 37(9), 1237-1250

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine ... [more ▼]

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations. Metabolic signatures of cancer cells and stroma were measured separately by MALDI-imaging, while metabolite changes in entire tumors were quantified using mass spectrometry approach. Measurement of glucose metabolism was also conducted in vivo using [18F]-fluorodeoxyglucose (FDG) and positron emission tomography (PET). In CRC/CRC-LM PDX model, human stroma was entirely replaced at the second generation. Despite this change, MALDI-imaging demonstrated that the metabolic profiles of both stromal and cancer cells remained stable for at least four generations in comparison to the original patient material. On the tumor level, profiles of 86 water-soluble metabolites as well as 93 lipid mediators underlined the functional stability of the PDX model. In vivo PET measurement of glucose uptake (reflecting tumor glucose metabolism) supported the ex vivo observations. Our data show for the first time that CRC/CRC-LM PDX model maintains the functional stability at the metabolic level despite the early replacement of the human stroma by murine cells. The findings demonstrate that human cancer cells actively educate murine stromal cells during PDX development to adopt the human-like phenotype. © 2017 Macmillan Publishers Limited, part of Springer Nature [less ▲]

Detailed reference viewed: 37 (14 ULiège)