Person: Lorente Pérez, María Del Mar
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First Name
María Del Mar
Last Name
Lorente Pérez
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
32 results
Search Results
Now showing 1 - 10 of 32
Item Optimization of a preclinical therapy of cannabinoids in combination with temozolomide against glioma(Biochemical Pharmacology, 2018) López-Valero, Israel; Torres, Sofía; Salazar Roa, María; García-Taboada, Elena; Hernández-Tiedra, Sonia; Guzmán Pastor, Manuel; Sepúlveda-Sánchez, Juan Manuel; Lorente Pérez, María Del Mar; Velasco Díez, Guillermo; Velasco Díez, GuillermoGlioblastoma multiforme (GBM) is the most frequent and aggressive form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease. Δ9-Tetrahydrocannabinol (THC, the major active ingredient of marijuana), and other cannabinoids have been shown to exert antitumoral actions in animal models of cancer, including glioma. The mechanism of these anticancer actions relies, at least in part, on the ability of these compounds to stimulate autophagy-mediated apoptosis in tumor cells. Previous observations from our group demonstrated that local administration of THC (or of THC + CBD at a 1:1 ratio, a mixture that resembles the composition of the cannabinoid-based medicine Sativex®) in combination with Temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. With the aim of optimizing the possible clinical utilization of cannabinoids in anti-GBM therapies, in this work we explored the anticancer efficacy of the systemic administration of cannabinoids in combination with TMZ in preclinical models of glioma. Our results show that oral administration of Sativex-like extracts (containing THC and CBD at a 1:1 ratio) in combination with TMZ produces a strong antitumoral effect in both subcutaneous and intracranial glioma cell-derived tumor xenografts. In contrast, combined administration of Sativex-like and BCNU (another alkylating agent used for the treatment of GBM which share structural similarities with the TMZ) did not show a stronger effect than individual treatments. Altogether, our findings support the notion that the combined administration of TMZ and oral cannabinoids could be therapeutically exploited for the management of GBM.Item Stimulation of ALK by the growth factor midkine renders glioma cells resistant to autophagy-mediated cell death(Autophagy, 2011) Lorente Pérez, María Del Mar; Torres, Sofia; Salazar Roa, María; Carracedo, Arkaitz; Hernández Tiedra, Sonia; Rodríguez Fornés, Fátima; García Taboada, Elena; Meléndez, Bárbara; Mollejo, Manuela; Campos Martín, Yolanda; Barcia Albacar, Juan Antonio; Guzmán Pastor, Manuel; Velasco Díez, Guillermo; Velasco Díez, GuillermoΔ9-tetrahydrocannabinol (THC), the main active component of marijuana, promotes cancer cell death via autophagy stimulation. We find that activation of the tyrosine kinase receptor ALK by its ligand midkine interferes with the signaling mechanism by which THC promotes autophagy-mediated glioma cell death.Item Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization(Autophagy, 2016) Salazar Roa, María; Guzmán Pastor, Manuel; Lorente Pérez, María Del Mar; Velasco Díez, Guillermo; Hernández Tiedra, Sonia; Fabriàs, Gemma; Dávila, David; Salanueva, Iñigo J.; Casas, Josefina; Montes, L.Ruth; Antón, Zuriñe; GarcíaTaboada, Elena; Nylandsted, Jesper; Armstrong, Jane; López Valero, Israel; McKee, Christopher S.; Serrano Puebla, Ana; García López, Roberto; González Martínez, José; Abad, José L.; Kentaro, Hanada; Boya, Patricia; Goñi, Félix; Lovat, Penny; Jäättelä, Marja; Alonso, AliciaAutophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used D9 -tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the regulatory mechanisms that determine the selective activation of autophagy-mediated cancer cell death.Item Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression(Cancer Research, 2008) Blázquez Ortiz, Cristina; Salazar Roa, María; Arkaitz Carracedo, Arkaitz; Lorente Pérez, María Del Mar; Egia, Ainara; Gonzalez Feria, Luis; Haro Ramos, Amador De; Velasco Díez, Guillermo; Guzmán Pastor, ManuelCannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis. It has also been reported that these compounds inhibit tumor cell spreading, but the molecular targets of this cannabinoid action remain elusive. Here, we evaluated the effect of cannabinoids on matrix metallopro- teinase (MMP) expression and its effect on tumor cell invasion. Local administration of #9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down- regulated MMP-2 expression in gliomas generated in mice, as determined by Western blot, immunofluorescence, and real-time quantitative PCR analyses. This cannabinoid- induced inhibition of MMP-2 expression in gliomas (a) was MMP-2–selective, as levels of other MMP family members were unaffected; (b) was mimicked by JWH-133, a CB2 cannabinoid receptor–selective agonist that is devoid of psychoactive side effects; (c) was abrogated by fumonisin B1, a selective inhibitor of ceramide biosynthesis; and (d) was also evident in two patients with recurrent glioblastoma multiforme. THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression by RNA interference and cDNA overexpression experiments proved that down-regulation of this MMP plays a critical role in THC- mediated inhibition of cell invasion. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knock- ing-down the expression of the stress protein p8. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down- regulation constitutes a new hallmark of cannabinoid anti- tumoral activity.Item Targeting Cannabinoid Receptors in Brain Tumors(Cannabinoids and the brain, 2008) Velasco Díez, Guillermo; Carracedo, Arkaitz; Blázquez Ortiz, Cristina; Lorente Pérez, María Del Mar; Aguado Sánchez, Tania; Sánchez García, María Cristina; Galve Roperh, Ismael; Guzmán Pastor, Manuel; Köfalvi, AttilaCannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances — the endocannabinoids — that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds as they kill glioma cells but not their nontransformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Δ9-tetrahydrocannabinol (Δ9-THC) in patients with recurrent glioblastoma multiforme has been recently run. The fair safety profile of Δ9-THC, together with its possible growth-inhibiting action on tumor cells, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.Item The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase(Clinical Cancer Research, 2016) Erazo, Tatiana ; Lorente Pérez, María Del Mar; Lopez-Plana, Anna ; Munoz-Guardiola, Pau; Fernandez-Nogueira, Patricia; García-Martínez, Jose; Bragado Domingo, Paloma; Fuster, Gemma ; Salazar Roa, María; Espadaler, Jordi ; Hernandez-Losa, Javier ; Bayascas, Jose Ramon ; Cortal, Marc ; Vidal, Laura ; Gascon, Pedro ; Gomez-Ferreria, Mariana ; Alfon, Jose ; Velasco Díez, Guillermo; Domenech, Carles ; Lizcano, JosePurpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.Item Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation(Cell Death and Differentiation, 2014) Salazar Roa, María; Lorente Pérez, María Del Mar; Garcia-Taboada, Elena; Pérez Gómez, Eduardo; Davila, Davila; Zuñiga, Patricia; Flores Landeira, Juana María; Rodriguez, Antonio; Hegedus, Zoltán; Mosen-Ansorena, David; Aransay, Ana María; Hernandez-Tiedra, Sonia; Lopez-Valero, Israël; Quintanilla, Miguel; Sanchez, Cristina; Iovanna, Juan; Dusetti, Nelson; Guzmán Pastor, Manuel; Francis, Sheila; Carracedo, Arkaitz; Kiss-Toth, Endre; Velasco Díez, GuillermoTribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumor- suppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axisItem Amphiregulin Is a Factor for Resistance of Glioma Cells to Cannabinoid-Induced Apoptosis(Glia, 2009) Lorente Pérez, María Del Mar; Carracedo, Arkaits; Torres, Sofia; Natali, Francesco; Egia, Ainara; Hernandez-Tiedra, Sonia; Salazar Roa, María; Blázquez Ortiz, Cristina; Guzmán Pastor, Manuel; Velasco Díez, Guillermo; Velasco Díez, GuillermoGliomas, one of the most malignant forms of cancer, exhibit high resistance to conventional therapies. Identification of the molecular mechanisms responsible for this resistance is therefore of great interest to improve the efficacy of the treatments against these tumors. D9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of can- cer, including glioma, an effect that relies, at least in part, on the ability of these compounds to induce apoptosis of tu- mor cells. By analyzing the gene expression profile of two sub-clones of C6 glioma cells with different sensitivity to cannabinoid-induced apoptosis, we found a subset of genes with a marked differential expression in the two sub-clones. Furthermore, we identified the epidermal growth factor re- ceptor ligand amphiregulin as a candidate factor to mediate the resistance of glioma cells to cannabinoid treatment. Amphiregulin was highly overexpressed in the cannabi- noid-resistant cell line, both in culture and in tumor xeno- grafts. Moreover, in vivo silencing of amphiregulin rendered the resistant tumors xenografts sensitive to cannabinoid antitumoral action. Amphiregulin expression was associ- ated with increased extracellular signal-regulated kinase (ERK) activation, which mediated the resistance to THC by blunting the expression of p8 and TRB3—two genes involved in cannabinoid-induced apoptosis of glioma cells. Our findings therefore identify Amphirregulin as a factor for resistance of glioma cells to THC-induced apoptosis and contribute to unraveling the molecular bases underlying the emerging notion that targeted inhibition of the EGFR pathway can improve the efficacy of antitumoral therapies.Item Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity?(Neuropharmacology, 2008) Sánchez-Camacho Blázquez, Cristina; Carracedo, Arkaitz; Salazar Roa, María; Lorente Pérez, María Del Mar; Egia, Ainara; González-Feria, Luis; Haro Ramos, Amador De; Velasco Díez, Guillermo; Guzmán Pastor, Manuel; Guzmán Pastor, ManuelCannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and inhibiting tumor angiogenesis. It has also been reported that cannabinoids inhibit tumor cell invasiveness, but the molecular targets of this cannabinoid action remain elusive. Here we evaluated the effects of cannabinoids on the expression of tissue inhibitors of metalloproteinases (TIMPs), which play critical roles in the acquisition of migrating and invasive capacities by tumor cells. Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated TIMP-1 expression in mice bearing subcutaneous gliomas, as determined by Western blot and immunofluorescence analyses. This cannabinoid-induced inhibition of TIMP-1 expression in gliomas (i) was mimicked by JWH-133, a selective CB2 cannabinoid receptor agonist that is devoid of psychoactive side effects, (ii) was abrogated by fumonisin B1, a selective inhibitor of ceramide synthesis de novo, and (iii) was also evident in two patients with recurrent glioblastoma multiforme (grade IV astrocytoma). THC also depressed TIMP-1 expression in cultures of various human glioma cell lines as well as in primary tumor cells obtained from a glioblastoma multiforme patient. This action was prevented by pharmacological blockade of ceramide biosynthesis and by knocking-down the expression of the stress protein p8. As TIMP-1 up-regulation is associated with high malignancy and negative prognosis of numerous cancers, TIMP-1 down-regulation may be a hallmark of cannabinoid-induced inhibition of glioma progression.Item POTEE promotes breast cancer cell malignancy by inducing invadopodia formation through the activation of SUMOylated Rac1(2023) Martínez‐López, Angélica; García Casas, Ana; Infante, Guiomar; González‐Fernández, Mónica; Salvador, Nélida; Lorente, Mar; Mendiburu‐Eliçabe, Marina; Gonzalez‐Moreno, Santiago ; Villarejo‐Campos, Pedro ; Malliri, Angeliki ; Lorente Pérez, María Del Mar; Velasco Díez, Guillermo; Castillo Lluva, SoniaTThe small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1) has been implicated in cancer progression and in the poor prognosis of various types of tumors. Rac1 SUMOylation occurs during epithelial-mesenchymal transition (EMT), and it is required for tumor cell migration and invasion. Here we identify POTEE (POTE Ankyrin domain family member E) as a novel Rac1-SUMO1 effector involved in breast cancer malignancy that controls invadopodium formation through the activation of Rac1-SUMO1. POTEE activates Rac1 in the invadopodium by recruiting TRIO-GEF (triple functional domain protein), and it induces tumor cell proliferation and metastasis in vitro and in vivo. We found that the co-localization of POTEE with Rac1 is correlated with more aggressive breast cancer subtypes. Given its role in tumor dissemination, the leading cause of cancer-related deaths, POTEE could represent a potential therapeutic target for these types of cancer.