Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment

Abstract

BackgroundNovel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors.MethodsExpression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluorescence in a tissue microarray (TMA) analysis of 380 ovarian cancers and associations with clinicopathological features were sought. The effect of glycolysis pathway inhibitors on the growth of a panel of ovarian cancer cell lines was assessed by use of the SRB proliferation assay. Combination studies were undertaken combining these inhibitors with cytotoxic agents.ResultsMean expression levels of GLUT1 and HKII were higher in high grade serous ovarian cancer (HGSOC), the most frequently occurring subtype, than in non-HGSOC. GLUT1 expression was also significantly higher in advanced stage (III/IV) ovarian cancer than early stage (I/II) disease. Growth dependency of ovarian cancer cells on glucose was demonstrated in a panel of ovarian cancer cell lines. Inhibitors of the glycolytic pathway (STF31, IOM-1190, 3PO and oxamic acid) attenuated cell proliferation in platinum-sensitive and platinum-resistant HGSOC cell line models in a concentration dependent manner. In combination with either cisplatin or paclitaxel, 3PO (a novel PFKFB3 inhibitor) enhanced the cytotoxic effect in both platinum sensitive and platinum resistant ovarian cancer cells. Furthermore, synergy was identified between STF31 (a novel GLUT1 inhibitor) or oxamic acid (an LDH inhibitor) when combined with metformin, an inhibitor of oxidative phosphorylation, resulting in marked inhibition of ovarian cancer cell growth.ConclusionsThe findings of this study provide further support for targeting the glycolytic pathway in ovarian cancer and several useful combinations were identified.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4521-4) contains supplementary material, which is available to authorized users.

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“…Importantly, high glycolytic activity is regarded as a metabolic hallmark of cancer. So, inhibition of glycolysis promotes death of cell and has gradually been a novel strategy [19][20][21]. At present, most studies focus on an inhibitor named 2-DG which can be phosphorylated by hexokinase.…”

Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

“…Therefore, targeting metabolism may serve as a novel therapeutic in many cancer types. Previous studies have implicated altered metabolic pathways in ovarian cancer (58,59), and multiple studies have targeted glycolytic enzymes for ovarian cancer treatment (60)(61)(62).…”

Enhanced Antitumor Effects of Follicle-Stimulating Hormone Receptor-Mediated Hexokinase-2 Depletion on Ovarian Cancer Mediated by A Shift in Glucose Metabolism

“…Highly invasive ovarian cancer cells present a more intensive glycolytic phenotype than less invasive ovarian cancer cells [37][38]. HK2 is crucial for aerobic glycolysis and is overexpressed in ovarian cancer [15][16][17].…”

“…HK2 overexpression has been observed in high-grade and advanced ovarian cancer and is correlated with early recurrence and short progression-free survival in ovarian cancer patients [15][16][17]. Inhibition or knockdown of HK2 signi cantly attenuated tumor growth and the dissemination of ovarian cancer…”