Abstract
Ovarian cancer is one of the most lethal gynecologic malignancies in women. Isoflurane is one of the volatile anesthetics used extensively for inhalational anesthesia and gynecological surgery. However, the effects of isoflurane on ovarian cancer have not been fully elucidated. It is widely studied that one of the biochemical fingerprints of cancer cells is the altered energy metabolism which is characterized by preferential dependence on glycolysis for energy production in an oxygen-independent manner. In the present study, we explored the roles of isoflurane in the regulation of cellular metabolism of ovarian cancer cells. We observed the glucose uptake, lactate production and extracellular acidification of two ovarian cancer cell lines, SKOV3 and TOV21G were significantly stimulated by isoflurane treatments at 1 and 2 h. The glycolysis enzymes, HK2, PKM2, and LDHA were up-regulated by isoflurane. We report that miR-21 was induced by isoflurane treatments in ovarian cancer cells, leading to the elevated AKT phosphorylation and up-regulation of glycolysis enzymes. In contrast, the mitochondrial functions were suppressed by isoflurane treatments: the oxygen consumption, mitochondrial membrane potential (MMP), and activities of complex I, II, and IV on the electron transport chain were significantly decreased under isoflurane treatments. Importantly, ovarian cancer cells become hypersensitive to glycolysis inhibitors with isoflurane pretreatments. The present study demonstrates that isoflurane treatments drive a metabolic switch of ovarian cancer cells and contributes to the discovery and development of clinical therapeutic agents against ovarian cancer.
Highlights
Ovarian cancer is one of the most lethal gynecologic malignancies in women [1,2]
Membranes were blocked with 5% nonfat milk in PBS containing 0.1% Tween-20 (PBS-T) for 1 h at room temperature, the membranes were incubated with antibodies against Glucose transporter 1 (GLUT1), PKM2, HK2, LDHA (Glycolysis Antibody Sampler Kit #8337, Cell Signaling, Danvers, MA, U.S.A.) and β-actin (#4970, Cell Signaling, Danvers, MA, U.S.A.) at 1:1000 dilution at 4◦C overnight
Isoflurane treatments promote the glycolytic rate in ovarian cancer cells Since the metabolic switch from oxidative phosphorylation to glycolysis is a unique characteristic of cancer [11,12], we started to assess the effects of isoflurane treatments on the glucose metabolism in ovarian cancer cells
Summary
Ovarian cancer is one of the most lethal gynecologic malignancies in women [1,2]. The origin and pathogenesis of epithelial ovarian cancer are still poorly understood they have long been investigated [2]. The optimal treatment of ovarian cancer is the combination of surgery and chemotherapy [3]. The cellular effects of isoflurane on cancer cell remain elusive. Isoflurane has been described as a stimulator in ovarian cancer cells [10]. We will explore the roles of isoflurane in the regulation of glycolysis and oxidative phosphorylation of human ovarian cancer cells. The potential mechanisms of how isoflurane may influence ovarian cancer cellular metabolism will be investigated. The human ovarian epithelial carcinoma cell lines SKOV3 and TOV21G were obtained from American Type Culture Collection (ATCC). Cells were transfected at a final concentration of 50 nM of anti-miR-21 or control antisense or pre-miR-21 using Lipofectamine RNAi MAX reagent (Thermo Fisher Scientific, Waltham, MA) according to the manufacturer’s instructions.
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