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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.
Highlights
Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment
We evaluated the levels of expression of four selected glycolytic targets (GLUT1, HKII, PKM2 and Lactate dehydrogenase A (LDHA)) in a large series of ovarian cancers to investigate possible associations with histological subtype and stage of disease
Expression of glycolytic enzymes in ovarian tumours and association with histological subtypes and stage To assess the variation in expression of key components of the glycolytic pathway in ovarian cancers, expression levels of Glucose transporter 1 (GLUT1), HKII, PKM2 and LDHA were investigated in a series of 380 ovarian tumours by Automated Quantitative Analysis (AQUA)
Summary
Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. Many cancer cells rely on glycolysis as their primary source of energy regardless of oxygen availability; the persistence of glycolysis in cancer cells even under aerobic conditions is termed aerobic glycolysis or the Warburg effect This metabolic alteration in tumours has been extensively demonstrated in a wide variety of cancers and considered a ‘hallmark’ of advanced malignancy [3,4,5]. As tumours grow and expand away from a functional blood supply, glycolysis is an evolutionary adaptation of cells to survive and thrive in a hypoxic environment [3, 7, 10] This reliance on glycolysis provides a possible therapeutic opportunity and the enzymes comprising the glycolytic pathway may be potential targets for cancer treatment [6, 10,11,12,13,14,15,16,17]. Several glycolytic inhibitors have emerged as exhibiting promising anticancer activity both in vitro and in vivo and a number have reached clinical trials [10,11,12,13, 16]
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