Sánchez del Campo Ferrer, Luis

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Sánchez del Campo Ferrer, Luis

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Sánchez del Campo Ferrer, Luis

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Universidad de Murcia. Departamento de Bioquímica y Biología MolecularA

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Open Access
Analysis of Dll4 regulation reveals a combinatorial rolefor Sox and Notch in arterial development
(National Academy of Sciences, 2013-07-01) Sacilotto, Natalia; Monteiro, Rui; Fritzsche, Martin; Becker, Philipp W.; Liu, Ke; Pinheiro, Philip; Ratnayakaa, Indrika; Davies, Benjamin; Goding, Colin R.; Patient, Roger; Bou Gharios, George; De Val, Sarah; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
The mechanisms by which arterial fate is established and main-tained are not clearly understood. Although a number of signalingpathways and transcriptional regulators have been implicated inarterio-venous differentiation, none are essential for arterialformation, and the manner in which widely expressed factorsmay achieve arterial-speciﬁc gene regulation is unclear. Using bothmouse and zebraﬁsh models, we demonstrate here that arterialspeciﬁcation is regulated combinatorially by Notch signaling andSoxF transcription factors, via direct transcriptional gene activa-tion. Through the identiﬁcation and characterization of two arte-rial endothelial cell-speciﬁc gene enhancers for the Notch ligandDelta-like ligand 4 (Dll4), we show that arterial Dll4 expressionrequires the direct binding of both the RBPJ/Notch intracellulardomain and SOXF transcription factors. Speciﬁc combinatorial,but not individual, loss of SOXF and RBPJ DNA binding ablatesall Dll4 enhancer-transgene expression despite the presence ofmultiple functional ETS binding sites, as does knockdown of sox7;sox18 in combination with loss of Notch signaling. Furthermore,triple knockdown of sox7, sox18 and rbpj also results in ablationof endogenous dll4 expression. Fascinatingly, this combinatorialablation leads to a loss of arterial markers and the absence of a de-tectable dorsal aorta, demonstrating the essential roles of SoxF andNotch, together, in the acquisition of arterial identity
Open Access
Editorial: Cell stress responses and metabolic reprogramming in skin diseases
(Frontiers, 2023-03-01) Bastonini, Emanuela; Kovacs, Daniela; Lotti, Fiorenza; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Despite being in the challenging age of personalized and precision medicine, specific responses to external stressors may ultimately converge on common cell reprogramming mechanisms belonging to heterogeneous pathologies that range from metabolic disorders to cancer. Cell metabolism plays a crucial role in all living organisms and it is closely intertwined with multiple biochemical pathways, which should not simply viewed as a means to an end, since metabolic intermediates themselves can have huge functional importance. It is now recognized that there are many more metabolites, acting as signaling regulators than genes in the human genome. Perturbations of cell metabolism play an important role in both health and disease and perhaps their causative role is still underestimated. Certainly, some of those pathophysiological dysfunctions can result in cutaneous disorders.
Open Access
Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
(MDPI, 2009-12-18) Sáez Ayala, Magalí; Chazarra Parres, Soledad; Cabezas Herrera, Juan; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) are potent inhibitors of DHFR with dissociation constants (K-D) of 0.9 and 1.8 mu M, respectively, while polyphenols lacking the ester bound gallate moiety [e.g., (-)-epigallocatechin (EGC) and (-)-epicatechin (EC)] did not bind to this enzyme. To avoid stability and bioavailability problems associated with tea catechins we synthesized a methylated derivative of ECG (3-O-(3,4,5-trimethoxybenzoyl)(-)-epicatechin; TMECG), which effectively binds to DHFR (K-D = 2.1 mu M). In alkaline solution, TMECG generates a stable quinone methide product that strongly binds to the enzyme with a K-D of 8.2 nM. Quercetin glucuronides also bind to DHFR but its effective binding was highly dependent of the sugar residue, with quercetin-3-xyloside being the stronger inhibitor of the enzyme with a K-D of 0.6 mu M. The finding that natural polyphenols are good inhibitors of human DHFR could explain the epidemiological data on their prophylactic effects for certain forms of cancer and open a possibility for the use of natural and synthetic polyphenols in cancer chemotherapy.
Open Access
Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy
(Springer Nature, 2023-11-23) Martí Díaz, Román; Navarro, Ana; Tolivia, Jorge; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Pancreatic cancer cells with mutant KRAS require strong basal autophagy for viability and growth. Here, we observed that some processes that allow the maintenance of basal autophagy in pancreatic cancer cells are controlled by protein methylation. Thus, by maintaining the methylation status of proteins such as PP2A and MRAS, these cells can sustain their autophagic activity. Protein methylation disruption by a hypomethylating treatment (HMT), which depletes cellular S-adenosylmethionine levels while inducing S-adenosylhomocysteine accumulation, resulted in autophagy inhibition and endoplasmic reticulum stress-induced apoptosis in pancreatic cancer cells. We observed that by reducing the membrane localization of MRAS, hypomethylation conditions produced an imbalance in KRAS signaling, resulting in the partial inactivation of ERK and hyperactivation of the PI3K/AKT–mTORC1 pathway. Interestingly, HMT impeded CRAF activation by disrupting the ternary SHOC2 complex (SHOC2/MRAS/PP1), which functions as a CRAF-S259 holophosphatase. The demethylation events that resulted in PP2A inactivation also favored autophagy inhibition by preventing ULK1 activation while restoring the cytoplasmic retention of the MiT/TFE transcription factors. Since autophagy provides pancreatic cancer cells with metabolic plasticity to cope with various metabolic stress conditions, while at the same time promoting their pathogenesis and resistance to KRAS pathway inhibitors, this hypomethylating treatment could represent a therapeutic opportunity for pancreatic adenocarcinomas.
Open Access
Acriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditions
(MDPI, 2020-12-31) Martí Díaz, Román; Cabezas Herrera, Juan; Goding, Colin; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Hypoxia-inducible factor (HIF)-1α is constitutively expressed in melanoma cells under normoxic conditions and its elevated expression correlates with the aggressiveness of melanoma tumors. Here, we used acriflavine, a potent inhibitor of HIF-1α dimerization, as a tool to investigate whether HIF-1α-regulated pathways contribute to the growth of melanoma cells under normoxia. We observed that acriflavine differentially modulated HIF-1α-regulated targets in melanoma under normoxic conditions, although acriflavine treatment resulted in over-expression of vascular endothelial growth factor (VEGF), its action clearly downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1), a well-known target of HIF-1α. Consequently, downregulation of PDK1 by acrifavine resulted in reduced glucose availability and suppression of the Warburg effect in melanoma cells. In addition, by inhibiting the AKT and RSK2 phosphorylation, acriflavine also avoided protective pathways necessary for survival under conditions of oxidative stress. Interestingly, we show that acriflavine targets activating transcription factor 4 (ATF4) for proteasomal degradation while suppressing the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and a melanoma oncogene. Since acriflavine treatment results in the consistent death of melanoma cells, our results suggest that inhibition of HIF-1α function in melanoma could open new avenues for the treatment of this deadly disease regardless of the hypoxic condition of the tumor.
Open Access
The critical role of alpha-folate receptor in the resistance of melanoma to methotrexate
(WILEY, 2009-01-10) Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Although methotrexate (MTX) is an effective drug for several types of cancer, it is not active against melanoma. Experiments following methotrexate treatment indicated a reduced accumulation of the drug in the cytosolic compartment in melanoma cells, suggesting that the mechanisms that control the transport and retention of this drug could be altered in melanoma. For this reason, we analyzed the presence and function of folate receptor-alpha (FR alpha) in melanoma cells. In this study, we have identified the presence of FR alpha in normal and pathological melanocytes and demonstrated that MTX is preferentially transported through this receptor in melanoma cells. FR alpha-induced endocytic transport of MTX, together with drug melanosomal sequestration and cellular exportation, ensures reduced accumulation of this cytotoxic compound in intracellular compartments. The critical role of FR alpha in this mechanism of resistance and the therapeutic consequences of these findings are also discussed.
Open Access
Directed Phenotype Switching as an Effective Antimelanoma Strategy
(Cell Press, 2013-06-20) Sáez Ayala, Magalí; Fernández Pérez, María Piedad; Chazarra Parres, Soledad; Freter, Rasmus; Middleton, Mark; Piñero Madrona, Antonio; Cabezas Herrera, Juan; Goding, Colin R.; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A; Cirugía, Pediatría y Obstetricia y Ginecología
Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation-associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(−)-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status.
Metadata only
Diseño, síntesis y actividad antitumoral de un inhibidor de la dihidrofolato reductasa, derivado de las catequinas del té, para el tratamiento del melanoma / Luis Sánchez del Campo Ferrer; director José Neptuno Rodríguez López.
(Murcia : Universidad de Murcia, Departamento de Bioquímica y Biología Molecular-A,, 2009) Sánchez del Campo Ferrer, Luis
Open Access
Lebein, a snake venom disintegrin, induces apoptosis in human melanoma cells
(MDPI, 2016-07-05) Hammouda, Manel B.; Zakraoui, Ons; Aloui, Zohra; Riahi-Chebbi, Ichrak; Karoui, Habib; Essafi Benkhadir, Khadija; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that are free of resistance mechanisms and side effects. Anti-neoplasic properties have been highlighted for different disintegrins from snake venom including Lebein; however, the exact effect of Lebein on melanoma has not yet been defined. In this study, we showed that Lebein blocks melanoma cell proliferation and induces a more differentiated phenotype with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and microphthalmia-associated transcription factor (MITF) overexpression. Melanoma cells became detached but were less invasive with upregulation of E-cadherin after Lebein exposure. Lebein induced a caspase-independent apoptotic program with apoptosis inducing factor (AIF), BCL-2-associated X protein (BAX) and Bim overexpression together with downregulation of B-cell lymphoma-2 (BCL-2). It generated a distinct response in reactive oxygen species (ROS) generation and p53 levels depending on the p53 cell line status (wild type or mutant). Therefore, we propose Lebein as a new candidate for development of potential therapies for melanoma.
Open Access
The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies
(Elsevier, 2021-08-13) Licari, Eugenia; Falletta, Paola; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
In recent years considerable progress has been made in identifying the impact of mRNA translation in tumour progression. Cancer cells hijack the pre-existing translation machinery to thrive under the adverse conditions originating from intrinsic oncogenic programs, that increase their energetic demand, and from the hostile microenvironment. A key translation program frequently dysregulated in cancer is the Integrated Stress Response, that reprograms translation by attenuating global protein synthesis to decrease metabolic demand while increasing translation of specific mRNAs that support survival, migration, immune escape. In this review we provide an overview of the Integrated Stress Response, emphasise its dual role during tumorigenesis and cancer progression, and highlight the therapeutic strategies available to target it.