TY - JOUR
T1 - Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumorpromoter metabolic state
AU - Santacatterina, Fulvio
AU - Sánchez-Cenizo, Laura
AU - Formentini, Laura
AU - Mobasher, Maysa A.
AU - Casas, Estela
AU - Rueda, Carlos B.
AU - Martínez-Reyes, Inmaculada
AU - de Arenas, Cristina Núñez
AU - García-Bermúdez, Javier
AU - Zapata, Juan M.
AU - Sánchez-Aragó, María
AU - Satrústegui, Jorgina
AU - Valverde, ángela M.
AU - Cuezva, José M.
N1 - Funding Information:
We thank Margarita Chamorro for expert technical support. LSC and FS were supported by pre-doctoral fellowships from FPI-MEC and FPI-UAM, respectively. LF was supported from AECC and Ramon and Cajal Program, Spain. This work was supported by Spanish grants from the MINECO (SAF2013-41945-R to JMC and SAF2012-33243 to AMV), CIBERER-ISCIII to JMC and CIBERDEM-ISCIII to AMV, Comunidad de Madrid (S2011/BMD-2402 to JMC and S2010/BMD-2423 to AMV), Fundación Ramón Areces (FRA) to JMC and EFSD and Amylin Paul Langerhans to AMV. The CBMSO receives an institutional grant from FRA, Spain.
Publisher Copyright:
© 2016. Oncotarget.
PY - 2016
Y1 - 2016
N2 - The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Offmice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the relevance of mitochondrial activity in hepatocarcinogenesis. The expression of hIF1 promotes the inhibition of OXPHOS in both Tet-On and Tet- Offmouse models and induces a state of metabolic preconditioning guided by the activation of the stress kinases AMPK and p38 MAPK. Expression of the transgene significantly augmented proliferation and apoptotic resistance of carcinoma cells, which contributed to an enhanced diethylnitrosamine-induced liver carcinogenesis. Moreover, the expression of hIF1 also diminished acetaminophen-induced apoptosis, which is unrelated to differences in permeability transition pore opening. Mechanistically, cell survival in hIF1-preconditioned hepatocytes results from a nuclear factor-erythroid 2-related factor (Nrf2)-guided antioxidant response. The results emphasize in vivo that a metabolic phenotype with a restrained OXPHOS in the liver is prone to the development of cancer.
AB - The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Offmice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the relevance of mitochondrial activity in hepatocarcinogenesis. The expression of hIF1 promotes the inhibition of OXPHOS in both Tet-On and Tet- Offmouse models and induces a state of metabolic preconditioning guided by the activation of the stress kinases AMPK and p38 MAPK. Expression of the transgene significantly augmented proliferation and apoptotic resistance of carcinoma cells, which contributed to an enhanced diethylnitrosamine-induced liver carcinogenesis. Moreover, the expression of hIF1 also diminished acetaminophen-induced apoptosis, which is unrelated to differences in permeability transition pore opening. Mechanistically, cell survival in hIF1-preconditioned hepatocytes results from a nuclear factor-erythroid 2-related factor (Nrf2)-guided antioxidant response. The results emphasize in vivo that a metabolic phenotype with a restrained OXPHOS in the liver is prone to the development of cancer.
KW - ATPase inhibitory factor 1
KW - Cancer
KW - Energy metabolism
KW - Mitochondria
KW - Reactive oxygen species
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U2 - 10.18632/ONCOTARGET.6357
DO - 10.18632/ONCOTARGET.6357
M3 - Article
C2 - 26595676
AN - SCOPUS:84979925809
SN - 1949-2553
VL - 7
SP - 490
EP - 508
JO - Oncotarget
JF - Oncotarget
IS - 1
ER -