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
  • 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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