Role for the ATPase inhibitory factor 1 in the environmental carcinogen-induced Warburg phenotype

Kévin Hardonnière (1) , Morgane Fernier (1) , Isabelle Gallais (1) , Baharia Mograbi (2) , Normand Podechard (1) , E. Le Ferrec (1) , Nathalie Grova (3) , Brice Appenzeller (3) , Agnès Burel (4) , Martine Chevanne (1) , Odile Sergent (1) , Laurence Huc (5) , Sylvie Bortoli (6) , Dominique Lagadic-Gossmann (1)

1 Irset - Institut de recherche en santé, environnement et travail
2 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
3 Laboratory of Analytical Human Biomonitoring-CRP-Santé
4 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
5 ToxAlim-COMICS - Contaminants & Stress Cellulaire
6 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire

Most tumors undergo metabolic reprogramming towards glycolysis, the so-called Warburg effect, to support growth and survival. Overexpression of IF1, the physiological inhibitor of the F0F1ATPase, has been related to this phenomenon and appears to be a relevant marker in cancer. Environmental contributions to cancer development are now widely accepted but little is known about the underlying intracellular mechanisms. Among the environmental pollutants humans are commonly exposed to, benzo[a] pyrene (B[a] P), the prototype molecule of polycyclic aromatic hydrocarbons (PAHs), is a well-known human carcinogen. Besides apoptotic signals, B[a] P can also induce survival signals in liver cells, both likely involved in cancer promotion. Our previous works showed that B[a] P elicited a Warburg-like effect, thus favoring cell survival. The present study aimed at further elucidating the molecular mechanisms involved in the B[a] P-induced metabolic reprogramming, by testing the possible involvement of IF1. We presently demonstrate, both in vitro and in vivo, that PAHs, especially B[a] P, strongly increase IF1 expression. Such an increase, which might rely on beta 2-adrenergic receptor activation, notably participates to the B[a] P-induced glycolytic shift and cell survival in liver cells. By identifying IF1 as a target of PAHs, this study provides new insights about how environmental factors may contribute to related carcinogenesis.

Keywords: Cancer metabolism; Predictive markers

Domains: Life Sciences [q-bio]; Cancer; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Genomics [q-bio.GN]

Kévin Hardonnière, Morgane Fernier, Isabelle Gallais, Baharia Mograbi, Normand Podechard, et al.. Role for the ATPase inhibitory factor 1 in the environmental carcinogen-induced Warburg phenotype. Scientific Reports, 2017, 7 (1), pp.195. ⟨10.1038/s41598-017-00269-7⟩. ⟨hal-01518808⟩