Final article is available at "wileyonlinelibrary.com" Takako Okamoto, Masaki Mandai, Noriomi Matsumura, Ken Yamaguchi, Hiroshi Kondoh, Yasuaki Amano, Tsukasa Baba, Junzo Hamanishi, Kaoru Abiko, Kenzo Kosaka, Susan K. Murphy, Seiichi Mori, Ikuo Konishi "Hepatocyte nuclear factor-1β (HNF-1β) promotes glucose uptake and glycolytic activity in ovarian clear cell carcinoma" Molecular Carcinogenesis 54:35–49 (2013) / 京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12804号 / 論医博第2076号 / 新制||医||1001(附属図書館) / 80848 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 武藤 学, 教授 稲垣 暢也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Ovarian cancer is a significant concern for women’s health as it is the most lethal of all gynaecological malignancies. One of the reasons for the high mortality of this disease is that traditionally used chemotherapeutic treatments tend to have poor initial or sustained efficacy against ovarian tumours. Resistance to such treatments may in part be mediated by autophagy, a cell survival process in which unnecessary or damaged components of the cytoplasm are engulfed within a double-membraned vesicle known as an autophagosome and ultimately degraded upon fusion of the autophagosome with a lysosome. Autophagy has been shown to be employed by cells to aid in their survival under stresses such as nutrient deprivation, hypoxia, chemotherapy treatment, and growth factor withdrawal. As these stresses are commonly encountered by ovarian cancer cells, it is possible that autophagy promotes ovarian cancer cell survival. This thesis aims to investigate which stimuli induce autophagy in ovarian cancer cells and whether or not this induction can promote cell survival. In addition, there is a particular focus on the comparison of autophagy utilization between subtypes of ovarian cancer, as the subtypes are in fact considered different diseases and may vary in their usage of autophagy. The first chapter of this thesis provides relevant background information on autophagy as well as ovarian cancer and its subtypes. In the second chapter, I describe studies in which tumours from a large cohort of patients with ovarian cancer are assessed for LC3A, a marker of autophagy, in addition to markers of other cellular processes including hypoxia. Here I found that LC3A was significantly associated with poor patient survival in patients with the clear cell subtype of ovarian cancer, but not other subtypes. I also found that LC3A expression was associated with markers of hypoxia in the clear cell patient tumours and that clear cell carcinoma cell lines preferentially induced autophagy in response to hypoxia in vitro as compared to cell lines of the high-grade serous subtype. These results indicate that clear cell ovarian tumours are uniquely dependent upon autophagy in response to hypoxia. In the third chapter, I investigated the autophagic response to treatment with the standard ovarian cancer chemotherapy drugs carboplatin and paclitaxel in a syngeneic mouse model of ovarian cancer. I found that these drugs did indeed induce autophagy and that the cancer cells utilized autophagy to promote resistance to these chemotherapeutics. In addition, when the tumour cells were grown in syngeneic mice, treatment with the autophagy inhibitor hydroxychloroquine resulted in a significant suppression of tumour growth. Together, my findings indicate that further investigation into the use of autophagy inhibitors in ovarian cancer patients is warranted and that different specific rational drug combinations for each subtype will likely yield optimal results. / Graduate

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19591号 / 医博第4098号 / 新制||医||1014(附属図書館) / 32627 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 武田 俊一, 教授 小川 修 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM