Cancer cells preferentially metabolise glucose via aerobic glycolysis (the Warburg effect), which is less energy efficient in teens of ATP production compared to oxidative phosphorylation (OXPHOS). Mitochondrial DNA (mtDNA) encodes proteins of the electron transfer chain and is crucial for functional OXPHOS. MtDNA exists as multiple copies in cells and, often in cancer, there is co-existence of mutant and wild-type mtDNA. There is evidence for mitochondria to contribute towards the tumor biology of multiple myeloma (MM) and glioblastoma multiforme (GBM). The mtDNA from both these cancer types were explored to determine its role in tumor biology. Sequencing of MM cells and tumor samples using the Ion Torrent next generation sequencer identified Cytochrome C Oxidase and ATP 6 to contain critical variants that are capable of disrupting protein function. Gene expression analysis determined that glycolysis is essential to maintaining MM cell proliferation. Without glycolysis, there was up-regulation in the expression of tumor survival genes, which was only effective in MM cells that had sufficient mtDNA copy numbers above the mtDNA set point. Sequencing of GBM cell lines, tumor and normal patient samples suggested that there is a predisposition of GBM tumors to acquire a set of GBM-specific mtDNA variants during tumor development. Conserved mtDNA regions, such as Cytochrome C Oxidase I, tend to be least susceptible to mutations. The presence of variants in these conserved regions carry more detrimental effects at the protein-level than at other mtDNA regions. Differentiation of GBM cells decreased the tumor phenotype, as assessed by gene expression analysis. Altogether, this thesis provides support for the importance of mtDNA in tumor biology. The implications are that the variants identified could be used to screen MM and GBM tumors in a clinical diagnostic lab for the treatment of both these cancer types.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:606215 |
| Date | January 2014 |
| Creators | Yeung, Ka Yu |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/62061/ |
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