Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival

• Published in: Oncotarget 2015-09, Vol.6 (28), p.26002-26017
• Main Authors: Amano, Yasuaki, Mandai, Masaki, Yamaguchi, Ken, Matsumura, Noriomi, Kharma, Budiman, Baba, Tsukasa, Abiko, Kaoru, Hamanishi, Junzo, Yoshioka, Yumiko, Konishi, Ikuo
• Format: Article
• Language: English
• Subjects: Adenocarcinoma, Clear Cell - genetics; Adenocarcinoma, Clear Cell - metabolism; Adenocarcinoma, Clear Cell - pathology; Amino Acid Transport Systems, Basic - genetics; Amino Acid Transport Systems, Basic - metabolism; Amino Acid Transport Systems, Neutral - genetics; Amino Acid Transport Systems, Neutral - metabolism; Antineoplastic Agents - pharmacology; Blotting, Western; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cell Survival - genetics; Cisplatin - pharmacology; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Glutathione - metabolism; Glutathione Disulfide - metabolism; Glycolysis - genetics; Hepatocyte Nuclear Factor 1-beta - genetics; Hepatocyte Nuclear Factor 1-beta - metabolism; Humans; Metabolome; Metabolomics - methods; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Reactive Oxygen Species - metabolism; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4692

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.