Intracellular oxygen concentration is regulated; however, due to technological limitations, most of our understanding of the regulation of oxygen at the cellular level has largely been limited to conclusions based on the enzyme kinetics of the iron-sulfur centers of the oxidative phosphorylation chain. This dissertation seeks to demonstrate control of intracellular oxygen concentration by the mitochondria using live cell microscopy with the oxygen sensing dye, acetylacetonatobis [2-(2'-benzothienyl) pyridinato-k N, kC3'] iridium (III) (BTP). Using this technique, it was revealed that less aggressive prostate cancer cell lines exhibit endogenous hypoxia, whereas, more aggressive cell lines are more endogenously normoxic. Cancer aggression, mitochondrial function, and endogenous oxygen conditions appeared to be well correlated. Indeed, as will be shown in the following chapters, high levels of mitochondrial respiratory function was observed to lead to the induction of endogenous hypoxia and this effect could be enhanced by exogenous hypoxia. Additionally, it was observed that intracellular oxygen concentration could be modulated by altertering mitochondrial activity through changes in glucose concentration and androgen availability. Finally, a common trait of cancer stem is high clonogenicity. Indeed, cell lines with reduced mitochondrial function exhibited increased clonogenic capacity compared to cell lines with higher levels of mitochondrial function. A common marker of cancer stem cell phenotype in prostate cancer is CD44 (a hyaluronan receptor) expression. Indeed, cell lines that were normoxic exhibited an increased population of CD44 expressing cells as determined by flow cytometery. CD44 expression cells in the sample population could be altered by changing extracellular oxygen concentration.
|Advisor:||Higuchi, Masahiro, Raney, Kevin|
|Commitee:||Chambers, Timothy, Kelly, Thomas, Wahls, Wayne|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 76/09(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Biochemistry|
|Keywords:||Cancer, Mitochondria, Oxygen, Prostate|
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