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

• DOI: 10.18632/oncotarget.14910
• Publication Date: 2017-02-01T20:20:36Z
• Authors: Charlotte Taylor; David Mannion; Fabrizio Miranda; Mohammad Karamine...; Sandra Herrero-Go...; Karin Hellner; Yiyan Zheng; Geoffrey Bartholo...; Robert C. Bast; Ahmed Ashour Ahmed
• Keywords: Mitotic catastrophe; Warburg Effect

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