Isobacachalcone induces autophagy and improves the outcome of immunogenic chemotherapy.
Qi WuAi-Ling TianSylvère DurandFanny AprahamianNitharsshini NirmalathasanWei XiePeng LiuLiwei ZhaoShuai ZhangHui PanDidac Carmona-GutierrezFrank MadeoYi TuOliver KeppGuido KroemerPublished in: Cell death & disease (2020)
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.
Keyphrases
- endoplasmic reticulum stress
- induced apoptosis
- signaling pathway
- cell death
- cell cycle arrest
- oxidative stress
- pi k akt
- immune response
- cell proliferation
- gene expression
- stem cells
- mouse model
- type diabetes
- insulin resistance
- wild type
- locally advanced
- peripheral blood
- copy number
- endoplasmic reticulum
- protein kinase
- chemotherapy induced