2. Academic Validation
  3. 3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB

3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB

  • EMBO Mol Med. 2019 Nov 7;11(11):e10469. doi: 10.15252/emmm.201910469.
Guo Chen 1 2 3 4 5 6,  Wei Xie 1 2 3 4 5 6 7,  Jihoon Nah 8,  Allan Sauvat 1 2 3 4 5 6,  Peng Liu 1 2 3 4 5 6,  Federico Pietrocola 1 2 3 4 5 6,  Valentina Sica 1 2 3 4 5 6,  Didac Carmona-Gutierrez 9 10,  Andreas Zimmermann 9 10,  Tobias Pendl 9,  Jelena Tadic 9,  Martina Bergmann 9,  Sebastian J Hofer 9 10,  Lana Domuz 9 11,  Sylvie Lachkar 1 2 3 4 5 6,  Maria Markaki 12,  Nektarios Tavernarakis 12 13,  Junichi Sadoshima 8,  Frank Madeo 9 10,  Oliver Kepp 1 2 3 4 5 6,  Guido Kroemer 1 2 3 4 5 6 14 15 16
Affiliations

Affiliations

  • 1 Gustave Roussy Cancer Campus, Villejuif, France.
  • 2 INSERM, UMR1138, Centre de Recherche des Cordeliers, Paris, France.
  • 3 Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
  • 4 Université de Paris, Paris, France.
  • 5 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
  • 6 Sorbonne Université, Paris, France.
  • 7 Faculté de Médecine, Université Paris-Saclay, Kremlin-Bicêtre, France.
  • 8 Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ, USA.
  • 9 LInstitute of Molecular Biosciences, University of Graz, Graz, Austria.
  • 10 BioTechMed-Graz, Graz, Austria.
  • 11 Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
  • 12 Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
  • 13 Medical School, University of Crete, Heraklion, Greece.
  • 14 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • 15 Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China.
  • 16 Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
PMID: 31609086 DOI: 10.15252/emmm.201910469
Abstract

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of Polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger Autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced Autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of Anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.

Keywords

TFEB; TFE3; caloric restriction; caloric restriction mimetic; cardioprotection.

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