12 results on '"Icard, Philippe"'
Search Results
2. Citrate targets FBPase and constitutes an emerging novel approach for cancer therapy
- Author
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Icard, Philippe, Fournel, Ludovic, Coquerel, Antoine, Gligorov, Joseph, Alifano, Marco, and Lincet, Hubert
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- 2018
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3. How Phosphofructokinase-1 Promotes PI3K and YAP/TAZ in Cancer: Therapeutic Perspectives.
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Simula, Luca, Alifano, Marco, and Icard, Philippe
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THERAPEUTICS ,CITRATES ,CELLULAR signal transduction ,WARBURG Effect (Oncology) ,TRANSFERASES ,TUMORS ,DRUG resistance in cancer cells - Abstract
Simple Summary: We propose that PFK1 promotes a positive feedback loop with PI3K/AKT and YAP/TAZ signaling pathways in cancer cells. Therefore, targeting PFK1 (or its product F-1,6-BP) could improve the efficacy of PI3K and YAP/TAZ inhibitors currently tested in clinical trials. To this aim, we suggest the use of citrate, which is a physiologic and potent inhibitor of PFK1. PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this "citrate strategy" efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER
+ and lung RAS-driven tumors in mice without apparent toxicities. [ABSTRACT FROM AUTHOR]- Published
- 2022
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4. Fructose-1,6-bisphosphate promotes PI3K and glycolysis in T cells?
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Icard, Philippe, Alifano, Marco, Donnadieu, Emmanuel, and Simula, Luca
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T cells , *GLYCOLYSIS , *PHOSPHATIDYLINOSITOL 3-kinases , *CANCER cells , *METABOLISM - Abstract
We propose that fructose-1,6-bisphosphate (F-1,6-BP) promotes a feedback loop between phosphofructokinase-1 (PFK1), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and PFK2/PFKFB3, which enhances aerobic glycolysis and sustains effector T (T eff) cell activation, while oxidative metabolism is concomitantly downregulated. This regulation, promoted by low citrate and mitochondrial ATP synthesis, also sustains the Warburg effect in cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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5. The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target
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Lincet Hubert, Icard Philippe, Biologie et Thérapies Innovantes des Cancers Localement Agressifs (BioTICLA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pasteur [Nice] (CHU), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Ligue Nationale Contre le Cancer (Comité 69), Service de Chirurgie Thoracique ( NICE - Chirurgie Thoracique ), CHU Nice, Biologie et Thérapies Innovantes des Cancers Localement Agressifs ( BioTICLA ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut des Sciences Pharmaceutiques et Biologiques ( ISPB ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Lincet, Hubert, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Cancer Research ,ATP citrate lyase ,Apoptosis ,Oxidative Phosphorylation ,Epigenesis, Genetic ,0302 clinical medicine ,Neoplasms ,Pharmacology (medical) ,Glycolysis ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Lipoic acid ,Prognosis ,Tumor aggressiveness ,Warburg effect ,3. Good health ,ATP-citrate lyase ,Infectious Diseases ,Oncology ,030220 oncology & carcinogenesis ,Intracellular ,medicine.drug ,medicine.medical_specialty ,Hydroxycitrate ,Citric Acid Cycle ,Biology ,Prognosis biomarker ,Citric Acid ,03 medical and health sciences ,Acetyl Coenzyme A ,Internal medicine ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Biomarkers, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Pharmacology ,Cisplatin ,Cancer ,medicine.disease ,030104 developmental biology ,Endocrinology ,Cancer cell ,ATP Citrate (pro-S)-Lyase ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Citrate ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O 2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin.
- Published
- 2016
6. ATP citrate lyase: A central metabolic enzyme in cancer.
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Icard, Philippe, Wu, Zherui, Fournel, Ludovic, Coquerel, Antoine, Lincet, Hubert, and Alifano, Marco
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NUCLEOTIDE synthesis , *CITRATES , *POLYAMINES , *OXIDATION-reduction reaction , *ENERGY metabolism , *LIPID synthesis , *HYDROXYCINNAMIC acids , *ANIMALS , *BIOCHEMISTRY , *COENZYMES , *PHENOMENOLOGY , *OXALIC acid , *TRANSFERASES , *TUMORS , *METABOLISM - Abstract
ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA. The first of these molecules supports protein acetylation, in particular that of histone, and de novo lipid synthesis, and the last one sustains the production of aspartate (required for nucleotide and polyamine synthesis) and the regeneration of NADPH,H+(consumed in redox reaction and biosynthesis). ACLY transcription is promoted by SREBP1, its activity is stabilized by acetylation and promoted by AKT phosphorylation (stimulated by growth factors and glucose abundance). ACLY plays a pivotal role in cancer metabolism through the potential deprivation of cytosolic citrate, a process promoting glycolysis through the enhancement of the activities of PFK 1 and 2 with concomitant activation of oncogenic drivers such as PI3K/AKT which activate ACLY and the Warburg effect in a feed-back loop. Pending the development of specific inhibitors and tailored methods for identifying which specific metabolism is involved in the development of each tumor, ACLY could be targeted by inhibitors such as hydroxycitrate and bempedoic acid. The administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies. [ABSTRACT FROM AUTHOR]
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- 2020
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7. The dual role of citrate in cancer.
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Icard, Philippe, Simula, Luca, Zahn, Grit, Alifano, Marco, and Mycielska, Maria E.
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CITRATES , *KREBS cycle , *LIPID synthesis , *BONE growth , *METABOLIC models - Abstract
Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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8. Inhibition of Mcl-1 expression by citrate enhances the effect of Bcl-xL inhibitors on human ovarian carcinoma cells.
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Lincet, Hubert, Kafara, Perrine, Giffard, Florence, Abeilard-Lemoisson, Edwige, Duval, Maryline, Louis, Marie-Hélène, Poulain, Laurent, and Icard, Philippe
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CANCER cells ,OVARIAN cancer ,CITRATES ,GENE expression ,APOPTOTIC protease-activating factor 1 - Abstract
The inhibition of two major anti-apoptotic proteins, Bcl-x
L and Mcl-1, appears essential to destroy chemoresistant cancer cells. We have studied their concomitant inhibition, using ABT 737 or siRNA targeting XL1 and citrate, a molecule which reduces the expression level of Mcl-1. Two cisplatin-chemoresistant ovarian cell lines (SKOV3 and IGROV1-R10) were exposed to ABT 737 or siRNA targeting XL1 and citrate at various individual concentrations, or combined. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. Mcl-1 expression was barely reduced when cells were exposed to citrate alone, whereas a mild reduction was observed after ABT 737 treatment. Concomitant inhibition of Bcl-xL and Mcl-1 using ABT 737 or siXL1 associated with citrate was far more effective in inhibiting cell proliferation and inducing cell death than treatment alone. Given that few, if any, specific inhibitors of Mcl-1 are currently available, anti-glycolytic agents such as citrate could be tested in association with synthetic inhibitors of Bcl-xL [ABSTRACT FROM AUTHOR]- Published
- 2013
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9. A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells
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Icard, Philippe and Lincet, Hubert
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PENTOSE phosphate pathway , *FATTY acid synthesis , *CANCER cells , *COENZYMES , *LACTIC acid , *GLUTAMINE , *NUCLEOTIDES , *CELL metabolism - Abstract
Abstract: Cancer cells increase glucose uptake and reject lactic acid even in the presence of oxygen (Warburg effect). This metabolism reorients glucose towards the pentose phosphate pathway for ribose synthesis and consumes great amounts of glutamine to sustain nucleotide and fatty acid synthesis. Oxygenated and hypoxic cells cooperate and use their environment in a manner that promotes their development. Coenzymes (NAD+, NADPH,H+) are required in abundance, whereas continuous consumption of ATP and citrate precludes the negative feedback of these molecules on glycolysis, a regulation supporting the Pasteur effect. Understanding the metabolism of cancer cells may help to develop new anti-cancer treatments. [Copyright &y& Elsevier]
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- 2012
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10. Understanding the central role of citrate in the metabolism of cancer cells
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Icard, Philippe, Poulain, Laurent, and Lincet, Hubert
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CANCER cell growth , *CITRATES , *METABOLIC regulation , *GLYCOLYSIS , *ACETYL-CoA synthetase , *DRUG therapy - Abstract
Abstract: Cancers cells strongly stimulate glycolysis and glutaminolysis for their biosynthesis. Pyruvate derived from glucose is preferentially diverted towards the production of lactic acid (Warburg effect). Citrate censors ATP production and controls strategic enzymes of anabolic and catabolic pathways through feedback reactions. Mitochondrial citrate diffuses in the cytosol to restore oxaloacetate and acetyl-CoA. Whereas acetyl-CoA serves de novo lipid synthesis and histone acetylation, OAA is derived towards lactate production via pyruvate and / or a vicious cycle reforming mitochondrial citrate. This cycle allows cancer cells to burn their host''s lipid and protein reserves in order to sustain their own biosynthesis pathways. In vitro, citrate has demonstrated anti-cancer properties when administered in excess, sensitizing cancer cells to chemotherapy. Understanding its central role is of particular relevance for the development of new strategies for counteracting cancer cell proliferation and overcoming chemoresistance. [Copyright &y& Elsevier]
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- 2012
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11. Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma?
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Icard, Philippe, Simula, Luca, Wu, Zherui, Berzan, Diana, Sogni, Philippe, Dohan, Anthony, Dautry, Raphael, Coquerel, Antoine, Lincet, Hubert, Loi, Mauro, and Fuks, David
- Abstract
Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis (NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis ("Warburg effect") in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this "Gordian Knot" in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this "citrate strategy" could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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12. Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update.
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Icard, Philippe, Coquerel, Antoine, Wu, Zherui, Gligorov, Joseph, Fuks, David, Fournel, Ludovic, Lincet, Hubert, and Simula, Luca
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ACETYLCOENZYME A , *GLYCOLYSIS , *CANCER cells , *CELL metabolism , *PROTEIN-tyrosine kinase inhibitors , *CITRATES , *NUCLEOTIDE synthesis - Abstract
Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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