Récepteur intracellulaire

Résumé

Les récepteurs intracellulaires sont des récepteurs situé à l'intérieur de la cellule plutôt que sur sa membrane plasmique. Les hormones thyroïdiennes et les hormones stéroïdiennes sont, par exemple, des hormones nécessitant des récepteurs intracellulaires. Il existe différents types de récepteurs intracellulaires. Par exemple, les récepteurs nucléaires sont situés sur la membrane du noyau cellulaire, alors que les récepteurs de l'inositol trisphosphate sont situés sur le réticulum endoplasmique. Les ligands qui se lient à ces récepteurs sont généralement soit des messagers secondaires intracellulaire tel l'inositol trisphosphate, soit des hormones lipophiles extracellulaires, telles les hormones stéroïdiennes. Quelques hormones peptidiques intracrines possèdent également un récepteur intracellulaire associé. Références Catégorie:Biochimie Catégorie:Récepteur

Source officielle

https://fr.wikipedia.org/wiki/R%C3%A9cepteur_intracellulaire

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Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

Malignant gliomas represent 80% of tumors developing in the central nervous system, with 50% being glioblastomas (GBM), the most aggressive form of the disease. The benefit from current therapies is very limited, the overall 5-year survival rate of patients with GBM being less than 5%. Thus, there is an urgent need for better therapies. It has been reported that the use of tricyclic antidepressants (TCAs) is linked with reduced incidence of gliomas. In line with these observations, our lab previously demonstrated that combining imipramine (IM), a TCA that activates adenylate cyclase and elevates production of cAMP, with ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y12 that otherwise suppresses cAMP, results in a concerted increase in the levels of intracellular cAMP, which consequently stimulates increased autophagy in glioma cells, leading to autophagy-associated cell death (AACD) in culture and during orthotopic tumor growth. In several mouse models of glioma, the combination improved survival and reduced malignant grade. Seeking to assess the therapeutic translational potential of these repurposed drugs, particularly IM, we performed pre-clinical trials combining IM+/-TIC with anti-VEGF therapy, which is commonly used in patients with GBM; such anti-angiogenic therapy is associated with a transitory improvement in progression-free survival and quality of life, but does not translate into an overall survival benefit. Using genetic mouse models with enabling bioluminescent monitoring of the cancer cells, we treated established GBMs with imipramine, ticlopidine, and B20S, an anti-mouse VEGF monoclonal antibody. We observed transient stabilization of tumor growth, and the overall survival was significantly extended in the regimens combining B20S with IM +/- TIC compared to control and single treatments. Similar to clinical observations in GBM patients treated with anti-angiogenic therapy, mice treated with B20S alone had no survival benefit, implicating a synergetic effect for the combination of anti-VEGF treatment with imipramine and ticlopidine. We found that the combinatorial therapy elicited further increases in autophagy and displayed some indication of blood vessel normalization, concomitant with an elevation of CD8+T lymphocyte infiltration into the orthotopic tumors. Notably, we could partially reverse the beneficial effect of the combinations using a CD8+T cell-depleting antibody, revealing the involvement of the recruited CD8+T cells in the efficacy of the combinatorial treatment, in addition to the cell-intrinsic autophagy-associated death that is demonstrable in culture and in tumors. Together, these results suggest a strategy to improve anti-angiogenic therapy in patients with glioblastoma, by using repurposed FDA-approved drugs that markedly elevate autophagy in concert with anti-VEGF therapy. The recruitment of CD8+ T cells into the treated tumors and their evident contribution to therapeutic efficacy motivates ongoing experiments aimed to heighten and sustain the induced anti-tumor immune response.

EPFL2018

Chargement

Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology

Hadrien Charles Edouard Demagny, Kristina Schoonjans, Yu Sun

Nuclear receptors play pleiotropic roles in cell differentiation, development, proliferation, and metabolic processes to govern liver physiology and pathology. The nuclear receptor, liver receptor homolog-1 (LRH-1, NR5A2), originally identified in the liver as a regulator of bile acid and cholesterol homeostasis, was recently recognized to coordinate a multitude of other hepatic metabolic processes, including glucose and lipid processing, methyl group sensing, and cellular stress responses. In this review, we summarize the physiological and pathophysiological functions of LRH-1 in the liver, as well as the molecular mechanisms underlying these processes. This review also focuses on the recent advances highlighting LRH-1 as an attractive target for liver-associated diseases, such as non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC).

2021

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The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPAR beta/delta was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPAR alpha, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPAR beta/delta and PPAR alpha to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPAR beta/delta and PPAR alpha participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor gamma (ERR gamma). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERR gamma on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

American Society for Clinical Investigation2013

Chargement

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

EPFL2018