Isoflurane promotes glucose metabolism through up-regulation of miR-21 and suppresses mitochondrial oxidative phosphorylation in ovarian cancer cells

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.