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

被引：79

作者：

Xintaropoulou, Chrysi ^{[1
,2
]}

Ward, Carol ^{[1
,2
,3
,4
]}

Wise, Alan ^{[5
]}

Queckborner, Suzanna ^{[1
,2
]}

Turnbull, Arran ^{[1
,2
]}

Michie, Caroline O. ^{[6
]}

Williams, Alistair R. W. ^{[7
]}

Rye, Tzyvia ^{[6
]}

Gourley, Charlie ^{[6
]}

Langdon, Simon P. ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Canc Res UK Edinburgh Ctr, Edinburgh EH4 2XU, Midlothian, Scotland

[2] Univ Edinburgh, Div Pathol Lab, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[3] Royal Dick Sch Vet Studies, Roslin EH25 9RG, Midlothian, Scotland

[4] Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland

[5] IOmet Pharma, Nine Edinburgh Bioquarter, Little France Rd, Edinburgh EH16 4UX, Midlothian, Scotland

[6] Univ Edinburgh, Canc Res UK Edinburgh Ctr, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[7] Univ Edinburgh, Div Pathol, Med Sch, 51 Little France Crescent, Edinburgh EH16 4SA, Midlothian, Scotland

来源：

BMC CANCER | 2018年 / 18卷

关键词：

Ovarian cancer; Glycolytic pathway; Inhibitors; Combination strategies; Cisplatin; Metformin; LACTATE-DEHYDROGENASE; DRUG-RESISTANCE; GLUCOSE TRANSPORTERS; EPITHELIAL TUMORS; BREAST-CANCER; HEXOKINASE-II; CELL-GROWTH; METFORMIN; INHIBITION; SURVIVAL;

D O I：

10.1186/s12885-018-4521-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Novel 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. Methods: Expression 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. Results: Mean 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. Conclusions: The findings of this study provide further support for targeting the glycolytic pathway in ovarian cancer and several useful combinations were identified.

引用

页数：15

共 80 条

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