The mitochondrial genome is often mutated and deleted in cancer development. Moreover, depletion of the mitochondrial genome progresses cancers to advanced phenotypes, however detailed mechanisms of the phenomenon have not been previously elucidated. The following dissertation presents, in vitro and in vivo, evidence that a reduction of mitochondrial genomic sequences is observed with the advanced progression of prostate cancer and breast cancer. Moreover, the dissertation describes experiments that demonstrated a cellular loss of mitochondrial genomic sequences reversibly induced the overexpression and activation of proto-oncogenic K-Ras 4A signals, which progressed cancers to advanced phenotypes. Ras activation was induced by overexpression of the rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR). Hypoxia is known to induce proteasomal degradation of HMGR. Well-differentiated prostate and breast cancer cells, which have a high copy number of the mitochondrial genome, consumed a large amount of oxygen and induced hypoxia; while a cellular loss of mitochondrial genomic sequences reduced oxygen consumption and thus increased the oxygen concentration in cells. The hypoxic-to-normoxic shift led to an overexpression of HMGR and, subsequently, an endogenous induction of the mevalonate pathway, which constitutively activated ras-signals that progressed the cancers to advanced phenotypes. Collectively, these results describe a coherent mechanism that directly links the cellular mitochondrial genome content with the advanced progression of cancers.
|Commitee:||Chambers, Timothy, Diekman, Alan, Douglas, Michael, Kelly, Thomas, McGehee, Robert|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Oncology|
|Keywords:||Breast cancer, Cancer progression, Mitochondria, Oxygen, Prostate cancer|
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