Research Papers:

Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells

Charlotte Taylor, David Mannion, Fabrizio Miranda, Mohammad Karaminejadranjbar, Sandra Herrero-Gonzalez, Karin Hellner, Yiyan Zheng, Geoffrey Bartholomeusz, Robert C. Bast Jr and Ahmed Ashour Ahmed _

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Oncotarget. 2017; 8:17960-17980. https://doi.org/10.18632/oncotarget.14910

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Charlotte Taylor1,2, David Mannion1,2, Fabrizio Miranda1,2, Mohammad Karaminejadranjbar1,2, Sandra Herrero-Gonzalez1,2, Karin Hellner1,2, Yiyan Zheng1,2, Geoffrey Bartholomeusz3, Robert C. Bast Jr3, Ahmed Ashour Ahmed1,2

1Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK

2Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK

3Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA

Correspondence to:

Ahmed Ashour Ahmed, email: [email protected]

Keywords: ovarian cancer, paclitaxel, mitotic arrest, PFKFB4, PFKFB3

Received: July 26, 2016    Accepted: December 15, 2016    Published: January 31, 2017


Taxanes represent some of the most commonly used chemotherapeutic agents for ovarian cancer treatment. However, they are only effective in approximately 40% of patients. Novel therapeutic strategies are required to potentiate their effect and improve patient outcome. A hallmark of many cancers is the constitutive activation of the PI3K/AKT pathway, which drives cell survival and metabolism. We discovered a striking decrease in AKT activity coupled with a significant reduction in glucose 6-phosphate and ATP levels during mitotic arrest in the majority of ovarian cancer cell lines tested, indicating a potential metabolic vulnerability. A high-content siRNA screen to detect novel metabolic targets in mitotically arrested ovarian cancer cells identified the glycolytic enzyme PFKFB4. PFKFB4 depletion increased caspase 3/7 activity, and levels of reactive oxygen species only in mitotically arrested cells, and significantly enhanced mitotic cell death after paclitaxel treatment. Depletion of PFKFB3 demonstrated a similar phenotype. The observation that some ovarian cancer cells lose AKT activity during mitotic arrest and become vulnerable to metabolic targeting is a new concept in cancer therapy. Thus, combining mitotic-targeted therapies with glycolytic inhibitors may act to potentiate the effects of antimitotics in ovarian cancer through mitosis-specific cell death.

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