Hyperglycemia-Associated Dysregulation of O-GlcNAcylation and HIF1A Reduces Anticancer Action of Metformin in Ovarian Cancer Cells (SKOV-3)

Abstract

Although cancer cells need more glucose than normal cells to maintain energy demand, chronic hyperglycemia induces metabolic alteration that may dysregulate signaling pathways, including the O-GlcNAcylation and HIF1A (Hypoxia-inducible factor 1-alpha) pathways. Metformin was demonstrated to evoke metabolic stress and induce cancer cell death. The aim of this study was to determine the cytotoxic efficiency of metformin on SKOV-3 cells cultured in hyperglycemia and normoglycemia. To identify the potential mechanism, we assessed the expression of O-linked β-N-acetlyglucosamine transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA), as well as hypoxia-inducible factor 1-alpha (HIF1A) and glucose transporters (GLUT1, GLUT3). SKOV-3 cells were cultured in normoglycaemia (NG, 5 mM) and hyperglycemia (HG, 25 mM) with and without 10 mM metformin for 24, 48, and 72 h. The proliferation rate, apoptotic and necrotic SKOV-3 cell death were evaluated. Real-Time qPCR was employed to determine mRNA expression of OGT, OGA, GLUT1, GLUT3, and HIF1A. Metformin significantly reduced the proliferation of SKOV-3 cells under normal glucose conditions. Whereas, the efficacy of metformin to induce SKOV-3 cell death was reduced in hyperglycemia. Both hyperglycemia and metformin induced changes in the expression of genes involved in the O-GlcNAcylation status and HIF1A pathway. The obtained results suggest that dysregulation of O-GlcNAcylation, and the related HIF1A pathway, via hyperglycemia, is responsible for the decreased cytotoxic efficiency of metformin in human ovarian cancer cells.

LncRNA-SNHG6 promotes the progression of hepatocellular carcinoma by targeting miR-6509-5p and HIF1A

“…Next, we conducted TargetScan analysis to investigate the potential protein targets of miR-6509-5p, and found the 3′UTR of hypoxia-inducible factor 1A (HIF1A) mRNA contained the binding sites for miR-6509-5p. HIF1A is known to regulate cellular adaption to hypoxic conditions and plays important roles in several cancers, including head and neck cancer, ovarian cancer and pancreatic cancer [24,35,36]. The remarkably decreased luciferase activities indicated the direct binding between miR-6509-5p and the 3′UTR of HIF1A mRNA.…”

MST1 Regulates Neuronal Cell Death via JNK/Casp3 Signaling Pathway in HFD Mouse Brain and HT22 Cells

“…Metabolic syndrome is a collection of evolving disorders that are characterized by insulin resistance, impaired glucose regulation, dyslipidemia, obesity, diabetes, and hypertension. Metabolic disorders are linked with brain disorders, including aging, Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative dementias [1,2,3,4]. In recent years, attempts have been made to investigate metabolic dysfunction in terms of impaired brain insulin signaling, high triglyceride and cholesterol concentrations, and mitochondrial dysfunction, which collectively lead to endoplasmic reticulum stress in neurons and to cognitive disorders [5,6,7,8].…”

Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via hsa-miR-542-5p

“…Thiamet-G is an inhibitor for OGA, administration of Thiamet-G could activate p53 and up-regulate downstream proteins expression in A2780 and SKOV-3 cells, indicating a potential therapy target for ovarian cancer treatment ( 29 ). Aneta Rogalska and colleagues found that abnormal OGT expression could induce ovarian cancer cell apoptosis ( 30 ). As a result, OGT and OGA play a pivotal role in tumor progression and prognosis.…”