Les agents mimant la restriction calorique et leur utilisation pour la chimioprévention métabolique

par Hui Chen

Projet de thèse en Sciences de la vie et de la santé

Sous la direction de Guido Kroemer.

Thèses en préparation à université Paris-Saclay , dans le cadre de École doctorale Cancérologie, Biologie, Médecine, Santé , en partenariat avec Métabolisme, Cancer et Immunité (laboratoire) , Apoptose, Cancer et Immunité (equipe de recherche) et de Faculté de médecine (référent) depuis le 30-09-2019 .

  • Résumé

    Certains agents mimant la restriction calorique comme l'aspirine et la spermidine réduisent l'incidence et la mortalités des cancers chez l'homme. Nous allons investiguer l'impact de tels agents sur le métabolisme, notamment dans le contexte de l'obésité (qui est antinomique à la restriction calorique) pour en déterminer les effets sur le métabolisme globale (et notamment le syndrome métabolique, le diabète et l'inflammation chronique), l'oncométabolisme (les particularités métaboliques des cellules cancéreuses) et l'immunométabolisme (le métabolisme des cellules du système immunité) et donc in fine en comprendre le mode d'action.

  • Titre traduit

    Caloric restriction mimetics for metabolic chemoprevention

  • Résumé

    Aging (time) is the most important risk factor for the development of most diseases including cancer. The team headed by Guido Kroemer launched the (still valid) hypothesis that most if not all longevity extending manipulations, be they genetic, pharmacological or metabolic, must induce autophagy to be efficient. The team identified spermidine as a novel, non-toxic inducer of autophagy and determined its mode of action as a life span-extending agent in yeast, nematodes, flies and mice. Guido Kroemer accumulated extensive evidence that acetyl coenzyme A and protein acetylation repress autophagy and that ‘caloric restriction mimetics' including spermidine induce autophagy via cytoplasmic deacetylation reactions, for instance by inhibition of the acetyltransferase EP300. Indeed, spermidine supplementation reduces cardiac morbidity and mortality in rodents and humans via the induction of autophagy. Moreover, the team discovered that aspirin acts as a pro-autophagic caloric restriction mimetic, explaining its cardioprotective and oncopreventive effects. The team developed phenotypic high-throughput screening systems to identify new caloric restriction mimetics and demonstrated that such agents, including several chalcones, actually confer autophagy-dependent life span extension and cardioprotection to flies and mice, respectively. In contrast, trans-unsaturated fatty acids inhibit autophagy induced by saturated fatty acids, perhaps explaining their cardiovascular toxicity. Guido Kroemer launched the hypothesis that life style factors that favor metabolic syndrome act through the inhibition of autophagy. Indeed, obesity is now known to be the most important risk factor for cancer development, right after tobacco, and obesity also constitutes a condition in which autophagy is inhibited and the aging process is accelerated. In contrast, epidemiological studies indicate that high nutritional uptake of spermidine (which is a natural food compound) and long-term medication of aspirin reduce the risk of malignant disease in humans. Based on this premises, it appears logical - yet remains to be demonstrated - that autophagy inhibition due to obesity might explain the procarcinogenic effects of excessive adiposity and that measures to avoid obesity and its comorbidities (and in particular the chronic administration of ‘caloric restriction mimetics') should avoid the obesity-associated increase in cancer incidence and progression. To explore this hypothesis, we will use several rodent models of obesity (such as high-fat diet administered to normal mice or normal chow fed to multated mice that spontaneously become obese, such as Ob/Ob and Foz/Foz mice), treat them with suitable ‘caloric restriction mimetics' (such as aspirin, chalcones, spermidine and others), monitor their impact on weight gain and metabolic syndrome-associated parameters (in particular diabetes and inflammation) and investigate their effect on oncogenesis (induced by urethane for lung carcinogenesis, azoxymethane (AOM)/dextran sulfate sodium (DSS) for colon carcinogenesis, medroxyprogesterone acetate (MPA)/7,12-Dimethylbenz[a]anthracene (DMBA) for breast carcinogenesis) or tumor progression (induced by subcutaneous or orthotopic injection of histocompatible cell lines). Theoretically, interventions on whole body metabolism may influence oncogenesis and cancer progression by effects of tumor metabolism (oncometabolism) or by a modulation of the immune system (immunometabolism). To distinguish between these two possibilities, we will study the impact of obesity-inducing and -preventive interventions on tumor development in immunocompetent and immunodeficient settings. Moreover, successful prophylactic or curative interventions with ‘caloric restriction mimetics' can be accompanied by measure to stimulate anticancer immune responses (in particular immune checkpoint blockade) to investigate their potential capacity to stimulate anticancer immunosurveillance.