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J. Biol. Chem., Vol. 281, Issue 2, 977-981, January 13, 2006

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Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth

OTTO WARBURG REVISITED^*

Tim J. Schulz||1, René Thierbach1, Anja Voigt, Gunnar Drewes, Brun Mietzner||, Pablo Steinberg, Andreas F. H. Pfeiffer¶, and Michael Ristow¶||2

From the German Institute of Human Nutrition Potsdam-Rehbrücke and Department of Nutritional Toxicology, Institute of Nutrition, University of Potsdam, Nuthetal D-14558, Germany, ^¶Charité University Medicine, Campus Benjamin Franklin, Berlin D-12203, Germany, ^||Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena 07743, Germany

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.

Received for publication, October 11, 2005

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (to M. R.), the Fritz-Thyssen-Stiftung (to M. R.), and the Leibniz-Gemeinschaft (to M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Human Nutrition, Institute for Nutrition, University of Jena, 29 Dornburger St., Jena 07743, Germany. Tel.: 49-3641-949630; Fax: 49-3641-949632; E-mail: michael.ristow{at}mristow.org.

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