1
Scientific RepoRts | 7: 195 | DOI:10.1038/s41598-017-00269-7
www.nature.com/scientificreports
Role for the ATPase inhibitory
factor 1 in the environmental
carcinogen-induced Warburg
phenotype
Kévin Hardonnière
1,2
, Morgane Fernier
1,2
, Isabelle Gallais
1,2
, Baharia Mograbi
3
, Normand
Podechard
1,2
, Eric Le Ferrec
1,2
, Nathalie Grova
4
, Brice Appenzeller
4
, Agnès Burel
2
, Martine
Chevanne
1,2
, Odile Sergent
1,2
, Laurence Huc
5
, Sylvie Bortoli
6
& Dominique Lagadic-
Gossmann
1,2
Most tumors undergo metabolic reprogramming towards glycolysis, the so-called Warburg eect, 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 eect, 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 β2-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.
e mitochondrial H
+
-ATP synthase, also called F0F1ATPase or complex V, is a master regulator of energy
production and cell fate
1–3
. Indeed, besides its well-recognized physiological role in oxidative phosphorylation
(OXPHOS) as the major cell producer of ATP, this enzyme has been implicated in the morphogenesis of mito-
chondrial cristae
4
, in the formation of the mitochondrial permeability transition pore (mPTP) during cell death
5
,
and the metabolic reprogramming of tumor cells
6
. Regarding this latter point, a decreased OXPHOS capacity and
subsequent drop in ATP synthesis due to complex V inhibition, appears to be responsible for a metabolic shi
towards aerobic glycolysis, which is better known as the Warburg eect
1
. In this context, OXPHOS inhibition is
oen linked to an apoptotic-resistant phenotype, and complex V regulation thus appears to be essential for tumor
progression
1, 6
.
Among the known regulators of the H
+
-ATP synthase, the physiological inhibitor ATP Inhibitory Factor 1
(IF1) has been implicated in the short-term regulation of energy metabolism by directly interacting with the βF1
subunit of this pump, whereby inhibiting its ATP hydrolysis activity
7
. IF1 protein, in its native form, is present
as a tetramer in mitochondrial matrix at a physiological matrix pH of ∼8.0. When matrix acidies, a release of
1
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France.
2
Université de Rennes
1, Biosit UMS3080, 35043, Rennes Cédex, France.
3
Institute of Research on Cancer and Ageing of Nice (IRCAN),
INSERM U1081, CNRS UMR7284, Université de Nice-Sophia Antipolis, Faculté de Médecine, Centre Antoine
Lacassagne, Nice, F-06107, France.
4
HBRU, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354, Esch-
sur-Alzette, Luxembourg.
5
INRA UMR 1331 ToxAlim, Toulouse, France.
6
INSERM UMR-S 1124, Université Paris
Descartes, Centre Universitaire des Saint-Pères, Paris, France. Correspondence and requests for materials should be
addressed to D.L. (email: dominique.lagadic@univ-rennes1.fr)
Received: 12 December 2016
Accepted: 14 February 2017
Published: xx xx xxxx
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