期刊
CELL DEATH & DISEASE
卷 11, 期 11, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-020-03226-x
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类别
资金
- Chinese scholarship council
- Scientific Research Training Program for Young Talents, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
- ile de France DIM ELICIT initiative
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR)-Projets blancs
- A.N.R.
- AMMICa US23/CNRS UMS3655
- Association pour la recherche sur le cancer (ARC)
- Association Le Cancer du Sein, Parlons-en
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR)
- Gustave Roussy Odyssea
- European Union Horizon 2020 Project Oncobiome
- Fondation Carrefour
- High-end Foreign Expert Program in China [GDW20171100085]
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology [ANR-18-IDEX-0001]
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Austrian Science Fund FWF [SFB-LIPOTOX F3007 F3012, W1226, P29203, P29262, P27893, P31727]
- Austrian Federal Ministry of Education, Science and Research
- University of Graz [BMWFW-80.109/0001-WF/V/3b/2015]
- NAWI Graz, the BioTechMed-Graz flagship project EPIAge
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 2 alpha (eIF2 alpha). Knockout of TFEB and/or TFE3 blunted the UPR, while knockout of PERK or replacement of eIF2 alpha 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.
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