Papers by Joana Relat Pardo
Cancers, 2020
Epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors (TKIs) are effective therapie... more Epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors (TKIs) are effective therapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor an EGFR activating mutation. However, this treatment is not curative due to primary and secondary resistance such as T790M mutation in exon 20. Recently, activation of transducer and activator of transcription 3 (STAT3) in NSCLC appeared as an alternative resistance mechanism allowing cancer cells to elude the EGFR signaling. Overexpression of fatty acid synthase (FASN), a multifunctional enzyme essential for endogenous lipogenesis, has been related to resistance and the regulation of the EGFR/Jak2/STAT signaling pathways. Using EGFR mutated (EGFRm) NSCLC sensitive and EGFR TKIs’ resistant models (Gefitinib Resistant, GR) we studied the role of the natural polyphenolic anti-FASN compound (−)-epigallocatechin-3-gallate (EGCG), and its derivative G28 to overcome EGFR TKIs’ resistance. We show that G28’s cytotoxicity is i...
International Journal of Molecular Sciences, 2019
The Fibroblast Growth Factor 21 (FGF21) is considered an attractive therapeutic target for obesit... more The Fibroblast Growth Factor 21 (FGF21) is considered an attractive therapeutic target for obesity and obesity-related disorders due to its beneficial effects in lipid and carbohydrate metabolism. FGF21 response is essential under stressful conditions and its metabolic effects depend on the inducer factor or stress condition. FGF21 seems to be the key signal which communicates and coordinates the metabolic response to reverse different nutritional stresses and restores the metabolic homeostasis. This review is focused on describing individually the FGF21-dependent metabolic response activated by some of the most common nutritional challenges, the signal pathways triggering this response, and the impact of this response on global homeostasis. We consider that this is essential knowledge to identify the potential role of FGF21 in the onset and progression of some of the most prevalent metabolic pathologies and to understand the potential of FGF21 as a target for these diseases. After ...
Molecules, 2018
Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer... more Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN), which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a family of EGCG derivatives and the lead compounds G28, G37 and G56 were characterized in HER2-positive breast cancer cells overexpressing FASN. Here, diesters G28, G37 and G56 and two G28 derivatives, monoesters M1 and M2, were synthesized and assessed in vitro for their cytotoxic, FASN inhibition and apoptotic activities in MDA-MB-231 triple-negative breast cancer (TNBC) cells. All compounds displayed moderate to high cytotoxicity and significantly blocked FASN activity, monoesters M1 and M2 being more potent inhibitors than diesters. Interestingly, G28, M1, and M2 also diminished FASN protein expression levels, but only monoesters M1 and M2 induced apoptosis. Our results indicate that FASN inhibition by such polyphenolic compounds could be a new strategy in TNBC treatment, and highlight the potential anticancer activities of monoesters. Thus, G28, G37, G56, and most importantly M1 and M2, are anticancer candidates (alone or in combination) to be further characterized in vitro and in vivo.
Molecular nutrition & food research, Aug 11, 2017
Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic candidate for the treat... more Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic candidate for the treatment of obesity. Since FGF21 production is regulated by various nutritional factors, we analyze the impact of low protein intake on circulating levels of this growth hormone in mice and in a sub cohort of the PREDIMED (Prevención con Dieta Mediterránea) trial. We also describe the role of hepatic FGF21 in metabolic adaptation to a low-protein diet (LPD). We fed control and liver-specific Fgf21 knockout (LFgf21KO) mice a LPD. This diet increased FGF21 production by inducing its overexpression in liver, and this correlated with a body weight decrease without changes in food intake. The LPD also caused FGF21-dependent browning in subcutaneous white adipose tissue (scWAT), as indicated by an increase in the expression of uncoupling protein 1 (UCP1). In a subgroup of 78 individuals from the PREDIMED trial, we observed an inverse correlation between protein intake and circulating FGF21 levels....
Hormone Molecular Biology and Clinical Investigation, 2016
Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast grow... more Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellu...
Anticancer research
The enzyme fatty acid synthase (FASN) is highly expressed in many human carcinomas and its inhibi... more The enzyme fatty acid synthase (FASN) is highly expressed in many human carcinomas and its inhibition is cytotoxic to human cancer cells. The use of FASN inhibitors has been limited until now by anorexia and weight loss, which is associated with the stimulation of fatty acid oxidation. The in vitro effect of (-)-epigallocatechin-3-gallate (EGCG) on fatty acid metabolism enzymes, on apoptosis and on cell signalling was evaluated. In vivo, the effect of EGCG on animal body weight was addressed. EGCG inhibited FASN activity, induced apoptosis and caused a marked decrease of human epidermal growth factor receptor 2 (HER2), phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular (signal)-regulated kinase (ERK) 1/2 proteins, in breast cancer cells. EGCG did not induce a stimulatory effect on CPT-1 activity in vitro (84% of control), or on animal body weight in vivo (99% of control). EGCG is a FASN inhibitor with anticancer activity which does not exhibit cross-activation of fatty acid ...
Journal of Medicinal Chemistry, 2012
Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human canc... more Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5−30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC 50 < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.
Journal of Lipid Research, 2013
Journal of Biological Chemistry, 2002
Pig and rat liver carnitine palmitoyltransferase I (L-CPTI) share common K m values for palmitoyl... more Pig and rat liver carnitine palmitoyltransferase I (L-CPTI) share common K m values for palmitoyl-CoA and carnitine. However, they differ widely in their sensitivity to malonyl-CoA inhibition. Thus, pig L-CPTI has an IC 50 for malonyl-CoA of 141 nM, while that of rat L-CPTI is 2 M. Using chimeras between rat L-CPTI and pig L-CPTI, we show that the entire C-terminal region behaves as a single domain, which dictates the overall malonyl-CoA sensitivity of this enzyme. The degree of malonyl-CoA sensitivity is determined by the structure adopted by this domain. Using deletion mutation analysis, we show that malonyl-CoA sensitivity also depends on the interaction of this single domain with the first 18 N-terminal amino acid residues. We conclude that pig and rat L-CPTI have different malonyl-CoA sensitivity, because the first 18 N-terminal amino acid residues interact differently with the C-terminal domain. This is the first study that describes how interactions between the C-and N-terminal regions can determine the malonyl-CoA sensitivity of L-CPTI enzymes using active Cterminal chimeras.
BMC Cancer, 2012
Background Fatty acid synthase (FASN) is overexpressed and hyperactivated in several human carcin... more Background Fatty acid synthase (FASN) is overexpressed and hyperactivated in several human carcinomas, including lung cancer. We characterize and compare the anti-cancer effects of the FASN inhibitors C75 and (−)-epigallocatechin-3-gallate (EGCG) in a lung cancer model. Methods We evaluated in vitro the effects of C75 and EGCG on fatty acid metabolism (FASN and CPT enzymes), cellular proliferation, apoptosis and cell signaling (EGFR, ERK1/2, AKT and mTOR) in human A549 lung carcinoma cells. In vivo, we evaluated their anti-tumour activity and their effect on body weight in a mice model of human adenocarcinoma xenograft. Results C75 and EGCG had comparable effects in blocking FASN activity (96,9% and 89,3% of inhibition, respectively). In contrast, EGCG had either no significant effect in CPT activity, the rate-limiting enzyme of fatty acid β-oxidation, while C75 stimulated CPT up to 130%. Treating lung cancer cells with EGCG or C75 induced apoptosis and affected EGFR-signaling. Whil...
Nutrients, 2020
The prevention and treatment of obesity is primary based on the follow-up of a healthy lifestyle,... more The prevention and treatment of obesity is primary based on the follow-up of a healthy lifestyle, which includes a healthy diet with an important presence of bioactive compounds such as polyphenols. For many years, the health benefits of polyphenols have been attributed to their anti-oxidant capacity as free radical scavengers. More recently it has been described that polyphenols activate other cell-signaling pathways that are not related to ROS production but rather involved in metabolic regulation. In this review, we have summarized the current knowledge in this field by focusing on the metabolic effects of flavonoids. Flavonoids are widely distributed in the plant kingdom where they are used for growing and defensing. They are structurally characterized by two benzene rings and a heterocyclic pyrone ring and based on the oxidation and saturation status of the heterocyclic ring flavonoids are grouped in seven different subclasses. The present work is focused on describing the mole...
Lenzim carnitina palmitoiltransferasa1 (CPT1), localitzat a la membrana mitocondrial externa, con... more Lenzim carnitina palmitoiltransferasa1 (CPT1), localitzat a la membrana mitocondrial externa, constitueix el principal punt de control de l'entrada d'acids grassos de cadena llarga (LCFA) al mitocondri i es clau en el manteniment dacids grassos circulants. Existeixen tres isotips descrits (CPT1A, CPT1B i CPT1C) que codifiquen per enzims amb diferents caracteristiques cinetiques i patrons dexpressio. 1.- Mecanismes de control transcripcional del gen CPT1B huma. El promotor huma de la CPT1B inclou un element de resposta a PPAR i un lloc dunio a MEF-2. Hem investigat el paper daquests elements de resposta i la possible interaccio entre PPARa i MEF2C en la regulacio transcripcional daquest promotor. Dels resultats obtinguts podem concloure que la resposta del promotor a PPARa depen: del context cellular, de lelement de resposta a MEF-2 i de la disposicio espacial daquest respecte al PPRE. La combinacio daquests elements cis en el promotor de la CPT1B indueix lexpressio maxima de...
The ability to detect changes in nutrient levels and generate an adequate response to these chang... more The ability to detect changes in nutrient levels and generate an adequate response to these changes is essential for the proper functioning of living organisms. Adaptation to the high degree of variability in nutrient intake requires precise control of metabolic pathways. Mammals have developed different mechanisms to detect the abundance of nutrients such as sugars, lipids and amino acids and provide an integrated response. These mechanisms include the control of gene expression (from transcription to translation). This review reports the main molecular mechanisms that connect nutrients' levels, gene expression and metabolism in health. The manuscript is focused on sugars' signaling through the carbohydrate-responsive element binding protein (ChREBP), the role of peroxisome proliferator-activated receptors (PPARs) in the response to fat and GCN2/activating transcription factor 4 (ATF4) and mTORC1 pathways that sense amino acid concentrations. Frequently, alterations in these pathways underlie the onset of several metabolic pathologies such as obesity, insulin resistance, type 2 diabetes, cardiovascular diseases or cancer. In this context, the complete understanding of these mechanisms may improve our knowledge of metabolic diseases and may offer new therapeutic approaches based on nutritional interventions and individual genetic makeup.
Muscle-type carnitine palmitoyltransferase 1 (CPT1b) is considered to be the gene that controls f... more Muscle-type carnitine palmitoyltransferase 1 (CPT1b) is considered to be the gene that controls fatty acid mitochondrial b-oxidation. A functional peroxisome proliferator-activated receptor (PPAR) responsive element (PPRE) and a myocite-specific (MEF2) site that binds MEF2A and MEF2C in the promoter of this gene had been previously identified. We investigated the roles of the PPRE and the MEF2 binding sites and the potential interaction between PPARa and MEF2C regulating the CPT1b gene promoter. Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1b promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1b gene promoter by MEF2C and PPARa-RXRa, a precise arrangement of its binding sites was essential.
Tdx, Mar 12, 2007
Als meus avis, als meus pares, a la Júlia i al Joan. Quan surts per fer el viatge cap a Ítaca, ha... more Als meus avis, als meus pares, a la Júlia i al Joan. Quan surts per fer el viatge cap a Ítaca, has de pregar que el camí sigui llarg, ple d'aventures, ple de coneixences. Has de pregar que el camí sigui llarg, que siguin moltes les matinades que entraràs en un port que els teus ulls ignoraven, i vagis a ciutats per aprendre dels que saben. Tingues sempre al cor la idea d'Ítaca. Has d'arribar-hi, és el teu destí, però no forcis gens la travessia. És preferible que duri molts anys, que siguis vell quan fondegis l'illa, ric de tot el que hauràs guanyat fent el camí, sense esperar que et doni més riqueses. Ítaca t'ha donat el bell viatge, sense ella no hauries sortit. I si la trobes pobra, no és que Ítaca t'hagi enganyat. Savi, com bé t'has fet, sabràs el que volen dir les Ítaques. (Kavafis-Carles Riba-Lluís Llach) Aquesta tesi ha estat realitzada gràcies a la concessió d
Trends in Pharmacological Sciences, 2013
Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging h... more Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective. This review outlines the nature of these regulatory mechanisms both in terms of their cellular specificity and probable effectiveness given the physiological paradigms in which thermogenesis is activated. Similarly, their potential for being targeted by new or existing drugs is discussed, drawing on the known mechanisms of action of various pharmacological agents and some probable limitations that should be considered.
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Papers by Joana Relat Pardo