title: Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival.
abstract: 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.
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Yasuaki
authors: Y
authors: Amano
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors: Masaki
authors: M
authors: Mandai
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Ken
authors: K
authors: Yamaguchi
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Noriomi
authors: N
authors: Matsumura
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Budiman
authors: B
authors: Kharma
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Tsukasa
authors: T
authors: Baba
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Kaoru
authors: K
authors: Abiko
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Junzo
authors: J
authors: Hamanishi
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Yumiko
authors: Y
authors: Yoshioka
authors: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Ikuo
authors: I
authors: Konishi
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C489857:SLC3A1 protein, human; D051539:Hepatocyte Nuclear Factor 1-beta; D005978:Glutathione; D002945:Cisplatin; D019803:Glutathione Disulfide
keywords: HNF1β; ROS; aerobic glycolysis; metabolome analysis; ovarian clear cell carcinoma