Abstract C60: IGF-1 signaling enhances mitochondrial activity and biogenesis in cancer cells independently of the glycolytic phenotype

Abstract

Abstract Cancer cells exhibit increases glycolytic rates and glucose transport to facilitate adaptation to the high energy demand imposed by increased proliferation rates and their often hypoxic environment. Moreover, this is often accompanied by reduced mitochondrial activity due to the accumulation of mtDNA mutations. Since there is close coordination of glycolysis and mitochondrial respiration, cancer cells may be particularly sensitive to pharmacological agents that increase mitochondrial activity. We recently identified a mitochondrial UTP transporter, PNC1, whose expression is induced by IGF-1 in an Akt-mTOR-dependant manner in transformed cells. PNC1 is a conserved orthologue of a yeast UTP carrier that is essential for maintenance of mtDNA replication and transcription and thereby mitochondrial biogenesis and activity. Suppression of PNC1 leads to increased mitochondrial ROS production, acquisition of an invasive phenotype, and mitochondrial biogenesis in cancer cells. Overexpression of PNC1 suppresses ROS production, mitochondrial biogenesis and protects from TGF-beta-induced epithelial-mesenchymal transition (EMT). The function of IGF-1-regulated PNC1 in cancer cells lead us to hypothesize that the IGF-1 signaling pathway may directly influence mitochondrial activity in cancer cells even in the presence of a switch to the glycolytic phenotype. Here we show that IGF-I stimulation increases mitochondrial mass in both normal cells and several cancer cell lines. The increased mitochondrial mass correlates with an increase in both mitochondrial protein and mRNA levels. This increase in mitochondrial biogenesis is also accompanied by increased oxygen consumption and ATP production. Furthermore, we show that the increase in both mitochondrial biogenesis and mitochondrial activity is due to IGF-1-mediated activation of a ROS-AMPK-PGC1 alpha signaling pathway. We conclude that mitochondrial activity and biogenesis in cancer cells is enhanced by the IGF-1 signaling pathway. Thus, attenuation of growth factor signaling may lead to accumulation of mtDNA damage and the consequent effects of increased ROS production on cancer cell phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C60.