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

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3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-10-14 , 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}

Affiliation

Gustave Roussy Cancer Campus, Villejuif, France.
INSERM, UMR1138, Centre de Recherche des Cordeliers, Paris, France.
Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
Université de Paris, Paris, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
Sorbonne Université, Paris, France.
Faculté de Médecine, Université Paris-Saclay, Kremlin-Bicêtre, France.
Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ, USA.
LInstitute of Molecular Biosciences, University of Graz, Graz, Austria.
BioTechMed-Graz, Graz, Austria.
Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.
Medical School, University of Crete, Heraklion, Greece.
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China.
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

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.

中文翻译：

3,4-二甲氧基查尔酮通过激活转录因子 TFE3 和 TFEB 诱导自噬。

热量限制模拟物（CRM）是天然或合成化合物，可模拟热量限制的促进健康和延长寿命的作用。CRM 引发细胞蛋白的脱乙酰化，并在无毒性的情况下与自噬通量的增加相结合。在这里，我们报告了在多酚库中鉴定出一种新的候选 CRM，即 3,4-二甲氧基查尔酮（3,4-DC）。当添加到几种不同的人类细胞系中时，3,4-DC 诱导细胞质蛋白的脱乙酰化并刺激自噬通量。然而，与其他特征明确的 CRM 不同，3,4-DC 需要转录因子 EB （TFEB）和 E3 （TFE3）依赖性基因转录和 mRNA 翻译来触发自噬。3,4-DC 在体外和体内、肝细胞和心肌细胞中刺激 TFEB 和 TFE3 转位到细胞核中。3,4-DC 在体外和小鼠器官中诱导自噬，介导自噬依赖性心脏保护作用，并提高体内抗癌化疗的疗效。总而言之，我们的结果表明 3,4-DC 是一种新型 CRM，具有以前未被识别的作用模式。

更新日期：2019-11-07

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