Targeting glucose metabolism as an anticancer strategy in ovarian cancer

Abstract

There has been a growing interest in cancer metabolism for targeted therapeutic approach for cancer, however

we still do not fully understand the signatures of metabolic alterations and modulating factors. In current studies, we provide novel insights of glucose metabolism and regulations in ovarian cancer. Resveratrol (RSV), a natural compound from grapes, selectively impairs glucose uptake via disruption of GLUT1 localization via suppression of the action of Akt in ovarian cancer cells. Inhibition of glucose uptake by RSV leads disruption of protein N-linked glycosylation (NLG) through suppression of hexosamine biosynthetic pathway, which regulated by GSK3β. Akt/GSK3β axis involves in RSV induced NLG disruption in ovarian cancer cells. Moreover, disruption of NLG by RSV leads to endoplasmic reticulum (ER) stress-mediated apoptosis in a cancer-specific manner. Mimicking glucose availabilities enhance cisplatin responses and suppress membrane expression of ATP-binding cassette transporters (ABC transporters), resulting from N-linked glycosylation (NLG) defect in drug-resistant ovarian cancer cells. NLG of ABC transporters is regulated by GSK3β activation through AMPK cascade in response to glucose limitation. Moreover, glucose deficiency attenuates the ovarian cancer stem-like cells (CSC) phenotypes, sphere forming capacities and stemness related gene expressions. Associated with that, glucose restriction suppresses Wnt/β-catenin signaling through decrease of β-catenin nuclear expression by GSK3β activation. Our findings provide evidence that glucose plays a pivotal role in controlling drug resistance in ovarian cancer. Hence, better understanding of differences in metabolic phenotypes between cancer cells and normal cells might offer to novel anticancer strategies.