Pyrimidine nucleotide carrier 1 in mitochondrial homeostasis and cancer

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Coleman, Michael
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University College Cork
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Abnormal metabolism has been a known feature of cancer for close to a decade, with mitochondrial dysfunction, aerobic glycolysis, and abnormal biosynthetic metabolism present in many cancers. Dysfunctional mitochondria alone have been shown to significantly influence cancer phenotype. Mitochondrial reprogramming has been demonstrated as an essential cancer cell survival response to diverse challenges. Our work has examined the significance of pyrimidine nucleotide carrier 1 (PNC1), an Insulin like Growth Factor 1 (IGF- 1)-inducible mitochondrial Uridine-5'-triphosphate (UTP) transporter in cancer. Loss of PNC1 is lethal, while suppression of PNC1 in cancer cells has been demonstrated to induce Epithelial to Mesenchymal Transition (EMT) driven by mitochondrial dysfunction and Reactive Oxygen Species (ROS). While PNC1 is ubiquitously expressed, PNC1 is frequently expressed at lower levels in solid tumours than in normal tissue. PNC1 can be suppressed by hypoxia, potentially through antagonism of MYC signalling. We also demonstrated that ectopic expression of PNC1 can revert the migratory phenotype of invasive MDA-MB-231 cells, and restore oxidative phosphorylation (OXPHOS) activity to these cells. These data suggest that the mitochondrial dysfunction present in these cells is partially due to their low PNC1 expression. Conversely, we observed that suppression of PNC1 in MCF-7 cells suppresses OXPHOS. Intriguingly, suppression of PNC1 impairs mitophagy in response to both mitochondrial depolarisation and hypoxia. We implicated disruption of the activity of the Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase Sirtuin 1 (SIRT1) in this impairment of mitophagy/autophagy. Crucially we observed strong support for these key findings in human cancer, where PNC1 expression is inversely correlated with markers of hypoxia signalling, and positively correlated with OXPHOS and autophagy. Overall the conclusion is that suppression of PNC1 in cancer may promote mitochondrial dysfunction, and critically, permit the persistence of dysfunctional mitochondria due to impaired mitophagy. Thus, reduced PNC1 expression has the potential to influence cancer phenotype.
Mitochondria , IGF-1 , PNC1 , SLC25A33 , Cancer , Breast , Mitophagy , Metabolism
Coleman, M. F. 2017. Pyrimidine nucleotide carrier 1 in mitochondrial homeostasis and cancer. PhD Thesis, University College Cork.