Abstract 3564: Silencing pfkfb2 enhances paclitaxel sensitivity by modulating metabolism of p53 wt ovarian and breast cancer cells and xenografts

Abstract

Abstract Breast cancer is the most common cause and epithelial ovarian cancer the fourth most common cause of cancer death among women in the developed world. While breast cancer can be cured in 70% of cases, only 30% of ovarian cancer patients remain free from disease long term. Paclitaxel is an integral component of primary therapy for both forms of cancer, but less than half of breast and ovarian cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. In recent years several kinases have been identified that regulate the sensitivity of cancer cells to paclitaxel by inhibiting centrosome splitting or enhancing microtubule stability. Much less attention has been given to kinases that affect paclitaxel sensitivity by modulating cancer cell metabolism. We previously performed siRNA kinome-screens to identify molecular targets whose decreased expression overcomes paclitaxel resistance and increases paclitaxel sensitivity in ovarian cancer cells. We showed that 20% of the potential kinase targets whose knockdown modulates paclitaxel sensitivity participate in glucose and energy metabolism. Among these, a leading candidate was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), an isoform of the glycolytic enzyme phosphofructokinase (PFK2). PFKFB2 is overexpressed in a fraction of ovarian and breast cancers. Knockdown of PFKFB2 inhibited clonogenic growth of ovarian and breast cancer cell lines and enhanced paclitaxel sensitivity in the cell lines with wt TP53. Liposome encapsulated PFKFB2 siRNA significantly inhibited tumor growth and enhanced sensitivity to paclitaxel in xenografts derived from ovarian cancer cell lines. Knockdown of PFKFB2 increased glycolysis, decreasing the flow of glycolytic intermediates to the pentose-phosphate pathway with reduced G6PD activity in wt TP53 cancer cell lines. With decreased NADPH, ROS accumulated after PFKFB2 knockdown, stimulating phosphorylation of JNK, inducing G1 cell cycle arrest, and initiating apoptosis dependent upon upregulation of p21Cip1 and Puma which are downstream targets of TP53. Our studies have shown for the first time that PFKFB2, a glycolytic enzyme, drives tumor cell growth and regulates paclitaxel sensitivity by inducing apoptosis and G1 cell cycle arrest. These findings highlight a remarkable degree of coordination between cancer metabolism with cell proliferation and chemo-sensitivity, which may provide a novel target in patients with ovarian cancers and breast cancers where TP53 function remains intact. Citation Format: Hailing Yang, Shu Zhang, Weiqun Mao, Ahmed A. Ahmed, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K. Sood, Xiao-Feng Le, Zhen Lu, Robert C. Bast. Silencing pfkfb2 enhances paclitaxel sensitivity by modulating metabolism of p53 wt ovarian and breast cancer cells and xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3564. doi:10.1158/1538-7445.AM2017-3564