Browsing by Author "Link, Wolfgang"
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- Adaptive mechanisms of resistance to antineoplastic agentsPublication . Ferreira, Bibiana; Lie, Maria K.; Engelsen, Agnete S. T.; Machado, Susana; Link, Wolfgang; Lorens, James B.Intrinsic and acquired resistance to conventional and targeted therapeutics is a fundamental reason for treatment failure in many cancer patients. Targeted approaches to overcome chemoresistance as well as resistance to targeted approaches require in depth understanding of the underlying molecular mechanisms. The anti-cancer activity of a drug can be limited by a broad variety of molecular events at different levels of drug action in a cell-autonomous and non-cell-autonomous manner. This review summarizes recent insights into the adaptive mechanisms used by tumours to resist therapy including cellular phenotypic plasticity, dynamic alterations of the tumour microenvironment, activation of redundant signal transduction pathways, modulation of drug target expression levels, and exploitation of pro-survival responses.
- Components and regulation of nuclear transport processesPublication . Cautain, Bastien; Hill, Richard; de Pedro, Nuria; Link, WolfgangThe spatial separation of DNA replication and gene transcription in the nucleus and protein translation in the cytoplasm is a uniform principle of eukaryotic cells. This compartmentalization imposes a requirement for a transport network of macromolecules to shuttle these components in and out of the nucleus. This nucleo-cytoplasmic transport of macromolecules is critical for both cell physiology and pathology. Consequently, investigating its regulation and disease-associated alterations can reveal novel therapeutic approaches to fight human diseases, such as cancer or viral infection. The characterization of the nuclear pore complex, the identification of transport signals and transport receptors, as well as the characterization of the Ran system (providing the energy source for efficient cargo transport) has greatly facilitated our understanding of the components, mechanisms and regulation of the nucleo-cytoplasmic transport of proteins in our cells. Here we review this knowledge with a specific emphasis on the selection of disease-relevant molecular targets for potential therapeutic intervention.
- CRISPR/Cas9‐mediated genome editing: from basic research to translational medicinePublication . Jacinto, Filipe; Link, Wolfgang; Ferreira, B IThe recent development of the CRISPR/Cas9 system as an efficient and accessible programmable genome-editing tool has revolutionized basic science research. CRISPR/Cas9 system-based technologies have armed researchers with new powerful tools to unveil the impact of genetics on disease development by enabling the creation of precise cellular and animal models of human diseases. The therapeutic potential of these technologies is tremendous, particularly in gene therapy, in which a patient-specific mutation is genetically corrected in order to treat human diseases that are untreatable with conventional therapies. However, the translation of CRISPR/Cas9 into the clinics will be challenging, since we still need to improve the efficiency, specificity and delivery of this technology. In this review, we focus on several in vitro, in vivo and ex vivo applications of the CRISPR/Cas9 system in human disease-focused research, explore the potential of this technology in translational medicine and discuss some of the major challenges for its future use in patients.
- Decavanadate and metformin-decavanadate effects in human melanoma cellsPublication . de Sousa-Coelho, Ana Luísa; Aureliano, Manuel; Fraqueza, Gil; Serrão, Gisela; Gonçalves, João; Sánchez-Lombardo, Irma; Link, Wolfgang; Ferreira, BibianaDecavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive-non-competitive inhibition with an IC50 value about 6 times higher (87 mu M) than the previously described for decavanadate (15 mu M). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/ threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways.
- Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic ShuttlingPublication . Cautain, Bastien; Castillo, Francisco; Musso, Loana; Ferreira, Bibiana; de Pedro, Nuria; Quesada, Lorena Rodriguez; Machado, Susana; Vicente, Francisca; Dallavalle, Sabrina; Link, WolfgangFOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines.
- DNA Methylation of PI3K/AKT pathway-related genes predicts outcome in patients with pancreatic cancer: a comprehensive bioinformatics-based studyPublication . Faleiro, Inês; Roberto, Vania Palma; Demirkol Canli, Secil; Fraunhoffer, Nicolas A.; Iovanna, Juan; Gure, Ali Osmay; Link, Wolfgang; Castelo-Branco, PedroPancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.
- FOXO family isoformsPublication . Santos, Bruno F; Grenho, Inês; Martel, Paulo; Ferreira, Bibiana; Link, WolfgangFOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.
- FOXO transcription factors as therapeutic targets in human diseasesPublication . Orea-Soufi, Alba; Paik, Jihye; Bragança, José; Donlon, Timothy A.; Willcox, Bradley J.; Link, WolfgangForkhead box (FOX)O proteins are transcription factors (TFs) with four members in mammals designated FOXO1, FOXO3, FOXO4, and FOXO6. FOXO TFs play a pivotal role in the cellular adaptation to diverse stress conditions. FOXO proteins act as context-dependent tumor suppressors and their dysregulation has been implicated in several age-related diseases. FOXO3 has been established as a major gene for human longevity. Accordingly, FOXO proteins have emerged as potential targets for the therapeutic development of drugs and geroprotectors. In this review, we provide an overview of the most recent advances in our under-standing of FOXO regulation and function in various pathological conditions. We discuss strategies targeting FOXOs directly or by the modulation of upstream regulators, shedding light on the most promising intervention points. We also reveal the most relevant clinical indications and discuss the potential, trends, and challenges of modulating FOXO activity for therapeutic purposes.
- FOXO transcription factors at the interface of metabolism and cancerPublication . Link, Wolfgang; Fernandez-Marcos, Pablo J.Diabetes refers to a group of metabolic diseases characterized by impaired insulin signalling and high blood glucose. A growing body of epidemiological evidence links diabetes to several types of cancer but the underlying molecular mechanisms are poorly understood. The signalling cascade connecting insulin and FOXO proteins provides a compelling example for a conserved pathway at the interface between insulin signalling and cancer. FOXOs are transcription factors that orchestrate programs of gene expression known to control a variety of processes in response to cellular stress. Genes regulated by this family of proteins are involved in the regulation of cellular energy production, oxidative stress resistance and cell viability and proliferation. Accordingly, FOXO factors have been shown to play an important role in the suppression of tumour growth and in the regulation of metabolic homeostasis. There is emerging evidence that deregulation of FOXO factors might account for the association between insulin resistance-related metabolic disorders and cancer.
- FOXO1 represses PPARα-Mediated induction of FGF21 gene expressionPublication . De Sousa-Coelho, Ana Luísa; Gacias, Mar; O'Neill, Brian T.; Relat, Joana; Link, Wolfgang; Haro, Diego; Marrero, Pedro F.Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARa and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARa. Here we show that FoxO1 represses PPARa-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARa target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARa and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARa-interacting protein that antagonizes PPARa activity on the FGF21 promoter. Because other PPARa target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARa-dependent manner. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
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