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Galluzzi L.,French Institute of Health and Medical Research | Galluzzi L.,University of Paris Descartes | Pietrocola F.,French Institute of Health and Medical Research | Bravo-San Pedro J.M.,French Institute of Health and Medical Research | And 28 more authors.
EMBO Journal | Year: 2015

Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy. Autophagy has been described to have tumor-suppressive as well as tumor-promoting functions. This review discusses how stage and context alters the role for autophagy in cancer, and argues for further research prior to targeting autophagy in cancer therapy. © 2015 The Authors.

Hernandez-Tiedra S.,Complutense University of Madrid | Hernandez-Tiedra S.,Institute Investigaciones Sanitarias San Carlos IdISSC | Fabrias G.,CSIC - Institute of Advanced Chemistry of Catalonia | Davila D.,Complutense University of Madrid | And 30 more authors.
Autophagy | Year: 2016

Autophagy 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 Δ9-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. © 2016 The Author(s). Association of American Geographers

Salazar M.,Complutense University of Madrid | Salazar M.,Institute Investigaciones Sanitarias San Carlos IdISSC | Salazar M.,Cell Division and Cancer Group | Lorente M.,Complutense University of Madrid | And 13 more authors.
Biochemical Society Transactions | Year: 2015

Tribbles pseudokinase 3 (TRIB3) belongs to the tribbles family of pseudokinases. In this article, we summarize several observation obtained by our laboratories supporting that TRIB3 plays a crucial role in the anti-cancer activity of cannabinoids (a novel family of potential anti-cancer agents derived from marijuana) and that TRIB3 genetic inactivation enhances cancer generation and progression. © 2015 Authors; published by Portland Press Limited.

Cianfanelli V.,Danish Cancer Society | Cianfanelli V.,Laboratory of Molecular Neuroembryology | Fuoco C.,University of Rome Tor Vergata | Lorente M.,Complutense University of Madrid | And 29 more authors.
Nature Cell Biology | Year: 2015

Inhibition of a main regulator of cell metabolism, the protein kinase mTOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these two mTOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA1, a member of the autophagy signalling network and a downstream target of mTOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene. © 2015 Macmillan Publishers Limited. All rights reserved.

Salazar M.,Complutense University of Madrid | Lorente M.,Complutense University of Madrid | Lorente M.,Institute Investigaciones Sanitarias San Carlos IdISSC | Garcia-Taboada E.,Complutense University of Madrid | And 11 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2013

Δ9-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 RasV 12/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 antineoplastic activity. This article is part of a Special Issue entitled Lipid Metabolism in Cancer. © 2013 Elsevier B.V. All rights reserved.

Salazar M.,Complutense University of Madrid | Salazar M.,Institute Investigaciones Sanitarias San Carlos IdISSC | Salazar M.,Cell Division and Cancer Group | Lorente M.,Complutense University of Madrid | And 31 more authors.
Cell Death and Differentiation | Year: 2015

Tribbles 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 axis. © 2015 Macmillan Publishers Limited All rights reserved.

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