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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23763号 / 医博第4809号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中島 貴子, 教授 戸井 雅和, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Normal cellular energy metabolism is fundamentally altered in cancer cells to facilitate rapid production of new cellular components, thereby enabling uncontrolled cell growth. Specifically, cancer cells rely on glycolysis and alternative pathways such as lipid and glutamine metabolism for energy, while diverting substrates away from oxidative metabolism regardless of the prevalence of oxygen in the microenvironment. This hallmark of cancer cells is referred to as the Warburg effect, the precise regulation of which is poorly understood despite several decades of research. In comparing the global gene expression profiles of ovarian cancer cells to those that overexpress Ets-1, we have revealed that this transcription factor is involved, at least in part, to this cancer-associated metabolic switch. To support the validity of these findings, we have shown that Ets-1 functionally regulates glycolytic dependence in ovarian and breast cancer cells, while concomitantly displaying a decreased capacity for oxidative phosphorylation. Reactive oxygen species are a normal byproduct of metabolism, and are produced excessively in cancer cells leading to oxidative stress. Interestingly, our genomic pathway analyses uncovered enrichments in antioxidant pathways associated with increased Ets-1 expression. Accordingly, we have also observed that Ets-1 regulates increased intracellular glutathione levels, and induces the activity of key antioxidant enzymes under oxidative stress. Sulfasalazine, an agent that restricts cystine uptake, was shown to be effective for decreasing these high glutathione levels during oxidative stress. These results are clinically relevant because high glutathione levels are associated with iii therapeutic resistance in cancer cells. Collectively, the evidence presented has identified a novel role for the transcription factor Ets-1 in the regulation of cancer energy metabolism, as well as the response to oxidative stress. We have also described a mechanism for Ets- 1-mediated therapeutic resistance, suggesting that this transcription factor may be a promising novel target to enhance conventional cancer therapies.</p> / Doctor of Philosophy (Medical Science)