TRIB3 suppresses tumorigenesis by controlling mTORC2/AKT/FOXO signaling.

In a recent article, we found that Tribbles pseudokinase 3 (TRIB3) plays a tumor suppressor role and that this effect relies on the dysregulation of the phosphorylation of v-akt murine thymoma viral oncogene homolog (AKT) by the mammalian target of rapamycin complex 2 (mTORC2 complex), and the subsequent hyperphosphorylation and inactivation of the transcription factor Forkhead box O3 (FOXO3)

A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma

Acknowledgments We thank Horacio Zimman and Carmen Moreno, from Hospital Clínico San Carlos, as well as Leyre Urigüen, from Universidad del Pais Vasco, for their kind collaboration in the processing and delivery of glioma samples; Dolores Hernán, Ana Isabel Torres, and Esther Gil for their contribution to the development of experiments with microparticles, and other members of our laboratory for their continuous support. Grant Support This work was supported by grants from Spanish Ministry of Science and Innovation (MICINN; PS09/01401; HF2005/0021, FR2009-0052, and IT2009-0053 to G. Velasco; SAF2006/00918 to M. Guzman), Santander-Complutense (PR34/07-15856 to G. Velasco), Comunidad de Madrid (S-SAL/0261/2006 and 950344 to M.G.), GW Pharmaceuticals (G. Velasco and M. Guzman), and Schering-Plough (G. Velasco). S. Torres was a recipient of a research training contract from Comunidad de Madrid; M. Lorente was sequentially a recipient of a “Juan de la Cierva” contract, a postdoctoral contract from Spanish Ministry of Education and Science and a postdoctoral contract from Comunidad de Madrid. F. Rodríguez-Fornés was a recipient of a fellowship from Schering-Plough and GW Pharmaceuticals; M. Hernández-Tiedra was a recipient of a fellowship from MEC and of a research training contract from Comunidad de Madrid; S. Hernández-Tiedra has a technician contract from MICINN and Fondo Social Europeo.Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM.Depto. de Bioquímica y Biología MolecularFac. de Ciencias BiológicasTRUEpu

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

Acknowledgements This work was supported by grants from Spanish Ministry of Science and Innovation (MICINN) (PS09/01401; HF2005/0021, FR2009-0052 and IT2009-0053 to GV; SAF2006/00918 to MG), Santander-Complutense (PR34/07-15856 to GV), Comunidad de Madrid (S-SAL/0261/2006 to MG). ML was sequentially the recipient of a ‘Juan de la Cierva’ contract, a postdoctoral contract from Spanish Ministry of Education and Science (MEC) and a postdoctoral contract from Comunidad de Madrid. ST was recipient of a research formation contract from Comunidad de Madrid, MS was recipient of a fellowship from MEC and of a research formation contract from Comunidad de Madrid, AC was recipient of fellowships from Gobierno Vasco, FEBS and EMBO. SH-T has a technician contract from MICINN and Fondo Social Europeo. We thank Horacio Zimman and Carmen Moreno from Hospital Clínico San Carlos as well as Leyre Urigüen from Universidad del Pais Vasco for their kind collaboration in the processing and delivery of glioma samples; Miguel Ángel Piris, Raquel Villuendas, Paloma Cueva and Rosa Pérez for technical advice in the gene expression experiments and other members of our lab for their continuous support.Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas.Depto. de Bioquímica y Biología MolecularFac. de Ciencias BiológicasTRUEpu

New religious movements

‘New religious movements’ (NRMs) is a term used to describe minority religions that have recently become visible in a society. They have appeared throughout the world and throughout history, and they have differed from each other with respect to their beliefs, practices, and lifestyles, as well as the effects they have on their members and on society. However, they do tend to consist of converts; to have a membership that is atypical of the rest of the population; to have a charismatic leader; to change more rapidly and radically than older, more established religions; and to evoke fear, suspicion, and, not infrequently, antagonism from nonmember

Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization

<p>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.</p

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas