Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival
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Yasuaki Amano1, Masaki Mandai1,2, Ken Yamaguchi1, Noriomi Matsumura1, Budiman Kharma1, Tsukasa Baba1, Kaoru Abiko1, Junzo Hamanishi1, Yumiko Yoshioka1, Ikuo Konishi1
1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
2Department of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan
Masaki Mandai, e-mail: [email protected]
Keywords: ovarian clear cell carcinoma, HNF1β, metabolome analysis, aerobic glycolysis, ROS
Received: February 24, 2015 Accepted: July 20, 2015 Published: July 31, 2015
HNF1β is expressed exclusively in ovarian clear cell carcinoma (OCCC) and not in other ovarian cancers, regarded as a hallmark of this tumor. This implies its central role in the unique character of OCCC, including resistance to chemotherapy, but its exact role and influence in cancer biology or the molecular bases of its function are largely unknown. Using comprehensive metabolome analysis of HNF1β_shRNA-stable cell lines, we show here that HNF1β drastically alters intracellular metabolism, especially in direction to enhance aerobic glycolysis, so called the “Warburg effect”. The consequence of the metabolic change contributed cell survival under stresses such as hypoxia and chemo-reagent, only when sufficient glucose supply was available. Augmented cell survival was based on the reduced ROS activity derived from metabolic alteration such as shift from oxidative phosphorylation to glycolysis and increased intracellular anti-oxidant, glutathione (GSH). One of the cystine transporters, rBAT is likely to play a major role in this GSH increase. These data suggest that HNF1β, possibly induced by stressful microenvironment in the endometriotic cyst, confers survival advantage to the epithelial cells, which leads to the occurrence of OCCC, a chemo-resistant phenotype of ovarian cancer.
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