Autophagy-mediated metabolic effects of aspirin

Francesca Castoldi (1, 2, 3) , Juliette Humeau (1, 2, 3) , Isabelle Martins (1, 2, 3) , Sylvie Lachkar (1, 2, 3) , Damarys Loew (4) , Florent Dingli (4) , Sylvère Durand (3) , David Enot (3) , Noëlie Bossut (3) , Alexis Chery (3) , Fanny Aprahamian (3) , Yohann Demont (1, 2, 3) , Paule Opolon (3, 5) , Nicolas Signolle (3, 5) , Allan Sauvat (1, 2, 3) , Michaela Semeraro (6) , Lucillia Bezu (1, 2, 3) , Elisa Elena Baracco (1, 2, 3) , Erika Vacchelli (1, 2, 3) , Jonathan Pol (1, 2, 3) , Sarah Lévesque (1, 2, 3) , Norma Bloy (7) , Valentina Sica (8) , Maria Chiara Maiuri (1, 2, 3) , Guido Kroemer (1, 2, 3, 9, 10) , Federico Pietrocola (11)

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 IUF - Institut universitaire de France
3 IGR - Institut Gustave Roussy
4 Laboratoire de Spectrométrie de Masse Protéomique
5 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
6 CIC 1419 - CIC - Mère Enfant Necker Cochin Paris Centre
7 Weill Medical College of Cornell University [New York]
8 UPF - Universitat Pompeu Fabra [Barcelona]
9 HEGP - Hôpital Européen Georges Pompidou [APHP]
10 Karolinska University Hospital [Stockholm]
11 Karolinska Institutet [Stockholm]

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.

Domaines: Sciences du Vivant [q-bio]

Francesca Castoldi, Juliette Humeau, Isabelle Martins, Sylvie Lachkar, Damarys Loew, et al.. Autophagy-mediated metabolic effects of aspirin. Cell Death Discovery, 2020, 6 (1), ⟨10.1038/s41420-020-00365-0⟩. ⟨hal-03050622⟩