Dépôt numérique

Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells

Kulbay, Merve, Johnson, Bruno, Ricaud, Guillaume, Séguin-Grignon, Marie-Noëlle et Bernier, Jacques ORCID: https://orcid.org/0000-0002-0594-5922 (2022). Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells Molecular and Cellular Biochemistry , vol. [ahead of . DOI: 10.1007/s11010-022-04433-0. (Sous Presse)

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DNA fragmentation factor 40 (DFF40), or the caspase-activated DNase (CAD), is an endonuclease specific for double-stranded DNA. Alterations in its function and expression have been linked to apoptosis resistance, a mechanism likely used by cancer cells. However, how the DFF40-related apoptosis resistance pathway occurs remains unclear. Here, we sought to determine if DFF40 expression could be linked to cell metabolism through the regulation of mitochondrial integrity and function. We demonstrated that DFF40-deficient cells are more resistant to staurosporine and tributyltin (TBT)-induced apoptosis, and express higher levels of Mcl-1 at basal state. Treatment with TBT induces higher Bcl-2 and caspase-9 mRNA transcripts in DFF40 KO Jurkat cells, as well as enhanced Bcl-2 phosphorylation. A loss of DFF40 expression induces a higher mitochondrial mass, mtDNA copy number, mitochondrial membrane potential, and glycolysis rates in resting T cells. DFF40-deficient cells exhibit the Warburg effect phenotype, where they rely significantly more on glycolysis than oxidative phosphorylation and have a higher proliferative state, demonstrated by a higher Ki-67 transcription factor expression and AKT phosphorylation. Finally, we demonstrated with cell fractioning that DFF40 can translocate to the mitochondria following apoptosis induction. Our study reveals that DFF40 may act as a regulator of mitochondria during cell death and its loss could compromise mitochondrial integrity and cause an energetic reprogramming in pathologies such as cancer.

Type de document: Article
Mots-clés libres: Apoptosis; Cancer; Cell proliferation; DFF40; DNA; Energetic metabolism; Mitochondria; Reprogramming; Warburg effect
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 10 juill. 2022 14:05
Dernière modification: 10 juill. 2022 14:05
URI: https://espace.inrs.ca/id/eprint/12764

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