Autophagy-mediated metabolic effects of aspirin.

Cell death discovery (2020-12-11)
Francesca Castoldi, Juliette Humeau, Isabelle Martins, Sylvie Lachkar, Damarys Loew, Florent Dingli, Sylvère Durand, David Enot, Noëlie Bossut, Alexis Chery, Fanny Aprahamian, Yohann Demont, Paule Opolon, Nicolas Signolle, Allan Sauvat, Michaela Semeraro, Lucillia Bezu, Elisa Elena Baracco, Erika Vacchelli, Jonathan G Pol, Sarah Lévesque, Norma Bloy, Valentina Sica, Maria Chiara Maiuri, Guido Kroemer, Federico Pietrocola
ABSTRACT

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b-/- or Bcln1+/-) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
TWEEN® 20, for molecular biology, viscous liquid
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D-(+)-Glucose, ≥99.5% (GC)
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Formaldehyde solution, for molecular biology, 36.5-38% in H2O
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Earle′s Balanced Salts, With sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Oxaliplatin, powder
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Trichostatin A, ≥98% (HPLC), from Streptomyces sp.
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Anacardic acid
Sigma-Aldrich
C646, ≥98% (HPLC)