Person: Lorente Pérez, María Del Mar
Loading...
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
19 results
Search Results
Now showing 1 - 10 of 19
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, Manuel; Manuel GuzmánCannabinoids, 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) Bragado Domingo, Paloma; Lorente Pérez, María Del Mar; Salazar Roa, María; Velasco Díez, Guillermo; Tatiana Erazo; Anna Lopez-Plana; Pau Munoz-Guardiola; Patricia Fernandez-Nogueira; Jose A. García-Martínez; Gemma Fuster; Jordi Espadaler; Javier Hernandez-Losa; Jose Ramon Bayascas; Marc Cortal; Laura Vidal; Pedro Gascon; Mariana Gomez-Ferreria; Jose Alfon; Carles Domenech; Jose M. Lizcano; Jose M. LizcanoPurpose: 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 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, 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 Amphiregulin Is a Factor for Resistance of Glioma Cells to Cannabinoid-Induced Apoptosis(Glia, 2009) Blázquez Ortiz, Cristina; Guzmán Pastor, Manuel; Lorente Pérez, María Del Mar; Salazar Roa, María; Velasco Díez, Guillermo; ARKAITZ CARRACEDO; SOFIA TORRES; FRANCESCO NATALI; AINARA EGIA; SONIA HERNANDEZ-TIEDRA; 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 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.Item Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide(Biochemical Pharmacology, 2018) López-Valero, Israel; Saiz-Ladera, Cristina; Torres, Sofía; Hernández-Tiedra, Sonia; García-Taboada, Elena; Rodríguez-Fornés, Fátima; Barba, Marina; Dávila, David; Salvador-Tormo, Nélida; Guzmán Pastor, Manuel; Sepúlveda, Juan Manuel; Sánchez-Gómez, Pilar; Lorente Pérez, María Del Mar; Velasco Díez, GuillermoGlioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease. Previous observations by our group and others have shown that Δ9-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas. We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide (TMZ), the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs. Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts. Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations – and specifically those containing a higher proportion of CBD – may be therapeutically explored to target the population of GICs in GBM.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 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 The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action(Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 2013) Salazar Roa, María; Lorente Pérez, María Del Mar; García-Taboada, Elena; Hernández-Tiedra, Sonia; Dávila, David; Francis, Sheila E.; Guzmán Pastor, Manuel; Kiss-Toth, Endre; Velasco Díez, Guillermo; Velasco Díez, GuillermoΔ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer. This effect relies, at least in part, on the up-regulation of several endoplasmic reticulum stress-related proteins including the pseudokinase tribbles homologue-3 (TRIB3), which leads in turn to the inhibition of the AKT/mTORC1 axis and the subsequent stimulation of autophagy-mediated apoptosis in tumor cells. Here, we took advantage of the use of cells derived from Trib3-deficient mice to investigate the precise mechanisms by which TRIB3 regulates the anti-cancer action of THC. Our data show that RasV12/E1A-transformed embryonic fibroblasts derived from Trib3-deficient mice are resistant to THC-induced cell death. We also show that genetic inactivation of this protein abolishes the ability of THC to inhibit the phosphorylation of AKT and several of its downstream targets, including those involved in the regulation of the AKT/mammalian target of rapamycin complex 1 (mTORC1) axis. Our data support the idea that THC-induced TRIB3 up-regulation inhibits AKT phosphorylation by regulating the accessibility of AKT to its upstream activatory kinase (the mammalian target of rapamycin complex 2; mTORC2). Finally, we found that tumors generated by inoculation of Trib3-deficient cells in nude mice are resistant to THC anticancer action. Altogether, the observations presented here strongly support that TRIB3 plays a crucial role on THC anti-neoplastic activity. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.