Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells.
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.
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Charlotte
C
Taylor
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
David
D
Mannion
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Fabrizio
F
Miranda
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Mohammad
M
Karaminejadranjbar
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Sandra
S
Herrero-Gonzalez
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Karin
K
Hellner
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Yiyan
Y
Zheng
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
Geoffrey
G
Bartholomeusz
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
Robert C
RC
Bast
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK.|Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Ahmed Ashour
AA
Ahmed
D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D025481:Phosphofructokinase-2 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D000970:Antineoplastic Agents; C506672:PFKFB4 protein, human; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel
PFKFB3; PFKFB4; mitotic arrest; ovarian cancer; paclitaxel