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.

Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis

“…It plays a role in repairing damage induced by oxidative stress in cancer cells and stops the process of cancer cachexia (36). Glutathione constitutes the survival advantage for cancer cells and is required for cancer initiation and progression (37,38). To date, a number of studies have demonstrated that the oxidant-antioxidant imbalance plays a critical role in the initiation and progression of multistage carcinogenesis of endometriosis (23,30,(39)(40)(41).…”

“…Second, HNF-1β actually reduces and protects cancer cells from oxidative stress by markedly changing antioxidant activity (78,81,82). HNF-1β may repair damage caused by oxidative stress and can promote survival by upregulating antioxidant proteins via binding with antioxidant response element (37,68,81,83,84). This gene upregulates the synthesis of glutathione (GSH), a powerful antioxidant (85).…”

Ovarian clear cell carcinoma meets metabolism; HNF-1β confers survival benefits through the Warburg effect and ROS reduction

“…To explore the intracellular metabolic change triggered by HNF1β expression, in the study in this issue of journal, we performed a comprehensive metabolite analysis (the metabolome assay) between HNF1β-high RMG2 and HNF1β_knockdown RMG2 cells [ 61 ]. As expected, repression of HNF1β expression caused drastic intracellular metabolic alteration.…”

Dynamic changes in the urine proteome in two ovarian cancer rat models

“…It was reported that overexpression of the glutamate-cysteine ligase catalytic subunit (GSH1) protects human ovarian cancer cells against oxidative and gamma-radiation-induced cell death [47] . Neutral and basic amino acid transport protein rBAT (SLC31) was reported to be a cysteine transporter and likely plays a major role in the increase of GSH [61] . Serum C-reactive protein (CRP) is a widely used biomarker of inflammation and has been previously shown to be a promising biomarker in patients with ovarian cancer [48] .…”