ANT2 expression under hypoxic conditions produces opposite cell-cycle behavior in 143B and HepG2 cancer cells.
Under hypoxic conditions, mitochondrial ATP production ceases, leaving cells entirely dependent on their glycolytic metabolism. The cytoplasmic and intramitochondrial ATP/ADP ratios, partly controlled by the adenine nucleotide translocator (ANT), are drastically modified. In dividing and growing cells that have a predominantly glycolytic metabolism, the ANT isoform 2, which has kinetic properties allowing ATP import into mitochondria, is over-expressed in comparison to control cells. We studied the cellular metabolic and proliferative response to hypoxia in two transformed human cell lines with different metabolic backgrounds: HepG2 and 143B, and in their rho(o) derivatives, i.e., cells with no mitochondrial DNA. Transformed 143B and rho(o) cells continued their proliferation whereas HepG2 cells, with a more differentiated phenotype, arrested their cell-cycle at the G(1)/S checkpoint. Hypoxia induced an increase in glycolytic activity, correlated to an induction of VEGF and hexokinase II (HK II) expression. Thus, according to their tumorigenicity, transformed cells may adopt one of two distinct behaviors to support hypoxic stress, i.e., proliferation or quiescence. Our study links the constitutive glycolytic activity and ANT2 expression levels of transformed cells with the loss of cell-cycle control after oxygen deprivation. ATP import by ANT2 allows cells to maintain their mitochondrial integrity while acquiring insensitivity to any alterations in the proteins involved in oxidative phosphorylation. This loss of cell dependence on oxidative metabolism is an important factor in the development of tumors.
INSERM E0018, Laboratoire de Biochimie et Biologie Moléculaire, CHU, Angers, France.
Arnaud
A
Chevrollier
Dominique
D
Loiseau
Fabien
F
Gautier
Yves
Y
Malthièry
Georges
G
Stepien
D033742:Adenine Nucleotide Translocator 2 / Q000235:genetics* / Q000378:metabolism; D033781:Adenine Nucleotide Translocator 3 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D033742:Adenine Nucleotide Translocator 2; D033781:Adenine Nucleotide Translocator 3; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D019344:Lactic Acid; D006593:Hexokinase; D005947:Glucose