Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited.
More than 80 years ago Otto Warburg suggested that cancer might be caused by a decrease in mitochondrial energy metabolism paralleled by an increase in glycolytic flux. In later years, it was shown that cancer cells exhibit multiple alterations in mitochondrial content, structure, function, and activity. We have stably overexpressed the Friedreich ataxia-associated protein frataxin in several colon cancer cell lines. These cells have increased oxidative metabolism, as shown by concurrent increases in aconitase activity, mitochondrial membrane potential, cellular respiration, and ATP content. Consistent with Warburg's hypothesis, we found that frataxin-overexpressing cells also have decreased growth rates and increased population doubling times, show inhibited colony formation capacity in soft agar assays, and exhibit a reduced capacity for tumor formation when injected into nude mice. Furthermore, overexpression of frataxin leads to an increased phosphorylation of the tumor suppressor p38 mitogen-activated protein kinase, as well as decreased phosphorylation of extracellular signal-regulated kinase. Taken together, these results support the view that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.
Schulz
Tim J
TJ
German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal.
Thierbach
René
R
Voigt
Anja
A
Drewes
Gunnar
G
Mietzner
Brun
B
Steinberg
Pablo
P
Pfeiffer
Andreas F H
AF
Ristow
Michael
M
D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry; D000362:Agar / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019069:Cell Respiration; D003110:Colonic Neoplasms / Q000378:metabolism; D004734:Energy Metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry* / Q000378:metabolism; D010101:Oxygen Consumption; D010766:Phosphorylation; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000096923:Frataxin
D000154:Aconitate Hydratase; D000255:Adenosine Triphosphate; D000362:Agar; D033862:Iron-Binding Proteins; D010100:Oxygen; D048051:p38 Mitogen-Activated Protein Kinases; D000096923:Frataxin