Induction of Oxidative Metabolism by Mitochondrial Frataxin Inhibits Cancer Growth

Abstract

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 signalregulated kinase. Taken together, these results support the view that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.Friedreich ataxia is an inherited neurodegenerative disorder (1) caused by the reduced expression of mitochondrial frataxin protein (2) leading to premature death due to cardiac failure (1), diabetes mellitus and insulin resistance (3), as well as impaired ATP synthesis in humans (4, 5). Concurrently it was shown that frataxin promotes oxidative metabolism and ATP synthesis when overexpressed in fibroblasts (6), possibly by a direct interaction with the respiratory chain (7). Although the primary function of frataxin is still a matter of debate (8), some evidence suggests that this protein directs the intramitochondrial synthesis of Fe/S clusters (9 -12). Individuals suffering from Friedreich ataxia have a reduced life expectancy of 38 years on average (1) and show increased oxidative stress (13-15). Overexpression of frataxin has been shown to reduce intracellular accumulation of reactive oxygen species (ROS) 3 and to prevent menadione-induced malignant transformation of fibroblasts (16). Furthermore, disruption of the frataxin homologue in yeast has been shown to cause increased sensitivity to oxidants and promote oxidative damage to both nuclear (17), as well as mitochondrial, DNA (18). In addition, fibroblasts from Friedreich ataxia patients exhibit increased sensitivity against ionizing radiation and show an increased frequency of transforming events (19). Although malignant disease is not considered a typical feature of the disorder, Friedreich ataxia patients exhibit various types of cancer atypical for their young age (reviewed in Refs. 3 and 16). Lastly, targeted disruption of frataxin in murine hepatocytes causes decreased life span and liver tumor formation in mice. 4 In parallel to these latter findings in rodents, we questioned whether frataxin migh...

Metabolic reprogramming of the tumor

“…Studies in mice, whose liver cells were devoid of frataxin, a mitochondrial protein that upregulates OXPHOS-mediated ATP synthesis, have shown a strong correlation between mitochondrial impairment and tumor promotion (Thierbach et al, 2005). Later in vitro studies found that overexpression of frataxin in colon cancer cell lines enhanced mitochondrial respiration and concomitantly diminished their tumorigenicity (Schulz et al, 2006). Similarly, genetic manipulation of the levels of PGC1a, a transcription factor whose activity fosters mitochondrial biogenesis, OXPHOS and fatty acid oxidation, revealed that knockout of PGC1a provokes intestinal tumor susceptibility whereas its overexpression hampers colorectal carcinogenesis (D'Errico et al, 2011).…”

P2X7: a growth-promoting receptor—implications for cancer

“…Neoplastic phenotype has often been associated to alterations in mitochondria physiology and morphology, to the point that a defect in oxidative phosphorylation was considered a hallmark of cancer [28,29]. Although there is no real indication that defective phosphorylation is an absolute feature of cancer cells, there is no doubt that many cancers display aerobic glycolysis.…”

Mitochondria and cancer: is there a morphological connection?

“…Several groups reported that tumour aggressiveness correlates with a low-mitochondrial respiratory chain activity, and that enhancement of OXPHOS can reduce tumour growth (Hervouet et al, 2005;Schulz et al, 2006). Furthermore, a number of mitochondrial enzyme deficiencies are linked to inherited neoplasia (Gottlieb and Tomlinson, 2005).…”