1. Isobacachalcone induces autophagy and improves the outcome of immunogenic chemotherapy
- Author
-
Wu, Qi, Tian, Ai-Ling, Durand, Sylvère, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Xie, Wei, Liu, Peng, Zhao, Liwei, Zhang, Shuai, Pan, Hui, Carmona-Gutierrez, Didac, Madeo, Frank, Tu, Yi, Kepp, Oliver, Kroemer, Guido, Wuhan University [China], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut Gustave Roussy (IGR), Université Paris-Saclay, University of Graz, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Karl-Franzens-Universität [Graz, Autriche], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Karl-Franzens-Universität Graz, and Gestionnaire, Hal Sorbonne Université
- Subjects
ANGELICA-KEISKEI ,[SDV]Life Sciences [q-bio] ,Immunosurveillance ,CALORIC RESTRICTION MIMETICS ,Biology and Life Sciences ,FLAVONOIDS ,Mice, Nude ,Article ,MECHANISMS ,[SDV] Life Sciences [q-bio] ,Mice ,Treatment Outcome ,CELL-DEATH ,CARDIOVASCULAR-DISEASE ,ISOBAVACHALCONE ,Macroautophagy ,Medicine and Health Sciences ,Autophagy ,Immunogenetics ,Animals ,Humans ,SEEDS ,TRAIL-INDUCED APOPTOSIS ,CHALCONES ,Signal Transduction - Abstract
International audience; A number of natural plant products have a long-standing history in both traditional and modern medical applications. Some secondary metabolites induce autophagy and mediate autophagy-dependent healthspan- and lifespan-extending effects in suitable mouse models. Here, we identified isobacachalcone (ISO) as a non-toxic inducer of autophagic flux that acts on human and mouse cells in vitro, as well as mouse organs in vivo. Mechanistically, ISO inhibits AKT as well as, downstream of AKT, the mechanistic target of rapamycin complex 1 (mTORC1), coupled to the activation of the pro-autophagic transcription factors EB (TFEB) and E3 (TFE3). Cells equipped with a constitutively active AKT mutant failed to activate autophagy. ISO also stimulated the AKT-repressible activation of all three arms of the unfolded stress response (UPR), including the PERK-dependent phosphorylation of eukaryotic initiation factor 2α (eIF2α). Knockout of TFEB and/or TFE3 blunted the UPR, while knockout of PERK or replacement of eIF2α by a non-phosphorylable mutant reduced TFEB/TFE3 activation and autophagy induced by ISO. This points to crosstalk between the UPR and autophagy. Of note, the administration of ISO to mice improved the efficacy of immunogenic anticancer chemotherapy. This effect relied on an improved T lymphocyte-dependent anticancer immune response and was lost upon constitutive AKT activation in, or deletion of the essential autophagy gene Atg5 from, the malignant cells. In conclusion, ISO is a bioavailable autophagy inducer that warrants further preclinical characterization.
- Published
- 2020