Person:
Lorente Pérez, María Del Mar

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First Name
María Del Mar
Last Name
Lorente Pérez
URI
https://hdl.handle.net/20.500.14352/76270
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
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2009 - 200912010 - 20161
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    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. Lizcano
    Purpose: 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.
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    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, Guillermo
    Gliomas, 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.