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6-Phosphofructo-2-Kinase/Fructose-2 Published OnlineFirst August 7, 2019; DOI: 10.1158/1078-0432.CCR-18-3448 Translational Cancer Mechanisms and Therapy Clinical Cancer Research 6-Phosphofructo-2-Kinase/Fructose-2,6- Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers Hailing Yang1, Zhang Shu1,2,Yongying Jiang3, Weiqun Mao1, Lan Pang1, Abena Redwood4, Sabrina L. Jeter-Jones4, Nicholas B. Jennings5, Argentina Ornelas6, Jinhua Zhou1, Cristian Rodriguez-Aguayo1,7, Geoffrey Bartholomeusz1, LaKesla R. Iles1, Niki M. Zacharias8, Steven W. Millward6, Gabriel Lopez-Berestein1,7, Xiao-Feng Le1, Ahmed A. Ahmed9,10, Helen Piwnica-Worms4, Anil K. Sood5,7, Robert C. Bast1, and Zhen Lu1 Abstract Purpose: Paclitaxel is an integral component of primary Results: Knockdown of PFKFB2 inhibited clonogenic therapy for breast and epithelial ovarian cancers, but less than growth and enhanced paclitaxel sensitivity in ovarian and half of these cancers respond to the drug. Enhancing the breast cancer cell lines with wild-type TP53 (wtTP53). response to primary therapy with paclitaxel could improve Silencing PFKFB2 significantly inhibited tumor growth and outcomes for women with both diseases. enhanced paclitaxel sensitivity in four xenografts derived Experimental Design: Twelve kinases that regulate from two ovarian and two breast cancer cell lines, and metabolism were depleted in multiple ovarian and breast prolonged survival in a triple-negative breast cancer PDX. cancer cell lines to determine whether they regulate sensi- Transfection of siPFKFB2 increased the glycolysis rate, but tivity to paclitaxel in Sulforhodamine B assays. The effects decreased the flow of intermediates through the pentose– of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase phosphate pathway in cancer cells with wtTP53,decreasing 2(PFKFB2) depletion on cell metabolomics, extracellular NADPH. ROS accumulated after PFKFB2 knockdown, which acidification rate, nicotinamide adenine dinucleotide phos- stimulated Jun N-terminal kinase and p53 phosphorylation, phate, reactive oxygen species (ROS), and apoptosis were and induced apoptosis that depended upon upregulation of studied in multiple ovarian and breast cancer cell lines. p21 and Puma. Four breast and ovarian human xenografts and a breast cancer Conclusions: PFKFB2 is a novel target whose inhibition patient-derived xenograft (PDX) were used to examine the can enhance the effect of paclitaxel-based primary chemo- knockdown effect of PFKFB2 on tumor cell growth in vivo. therapy upon ovarian and breast cancers retaining wtTP53. Introduction breast and ovarian cancers. Somatic TP53 mutations occur in over Paclitaxel has emerged as an important agent for adjuvant 50% of all tumors (4, 5), across nearly all types of cancer. TP53 treatment of both ovarian and breast cancers. When used as a mediates multiple processes, of which the best understood include single agent, however,lessthan half of these cancers respond (1–3). cell-cycle arrest, DNA repair, and apoptosis (6, 7). Recent work Enhancing the response to primary therapy with paclitaxel could indicates that TP53 has an important role in modulating metabolic improve outcomes for women with both diseases. The tumor processes including glycolysis, oxidative phosphorylation, and the suppressor TP53 is frequently mutated in human cancers including pentose–phosphate pathway (PPP; refs. 8, 9). 1Department of Experimental Therapeutics, University of Texas, MD Anderson Kingdom. 10Nuffield Department of Women's & Reproductive Health, University Cancer Center, Houston, Texas. 2Department of Geriatric Digestive Surgery, the of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, United Kingdom. 3 Second Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Institute for Note: Supplementary data for this article are available at Clinical Cancer Applied Cancer Science, University of Texas, MD Anderson Cancer Center, Research Online (http://clincancerres.aacrjournals.org/). Houston, Texas. 4Department of Experimental Radiation Oncology, University Corresponding Authors: Robert C. Bast, University of Texas MD Anderson of Texas, MD Anderson Cancer Center, Houston, Texas. 5Department of Gyne- Cancer Center, 1400 Pressler Street, FCT 8.5066, Houston 77030, TX. Phone: 713- cologic Oncology and Reproductive Medicine, University of Texas, MD Anderson 792-7743; Fax: 713-792-7864; E-mail: [email protected]; and Zhen Lu, Cancer Center, Houston, Texas. 6Cancer Systems Imaging, University of Texas, [email protected] MD Anderson Cancer Center, Houston, Texas. 7Center for RNA Interference and Non-Coding RNA Cancer, University of Texas, MD Anderson Cancer Center, Clin Cancer Res 2019;25:5702–16 Houston, Texas. 8Department of Urology, University of Texas, MD Anderson doi: 10.1158/1078-0432.CCR-18-3448 Cancer Center, Houston, Texas. 9Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, United Ó2019 American Association for Cancer Research. 5702 Clin Cancer Res; 25(18) September 15, 2019 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst August 7, 2019; DOI: 10.1158/1078-0432.CCR-18-3448 PFKFB2 Knockdown Enhances Paclitaxel Sensitivity are the key molecules for oxidative phosphorylation and apop- Translational Relevance tosis in mitochondria. PFKFB2 and PFKFB4 belong to a family of Breast cancer is the most common cause of cancer-related bifunctional enzymes that control the levels of fructose death and epithelial ovarian cancer the fourth most common 2,6-bisphosphate. Several studies have demonstrated that cause among women in the developed world. Paclitaxel-based some cancer cell lines produce markedly elevated level of chemotherapy continues to be an integral component in the fructose-2,6 bisphosphate (24, 25). Among these four genes, treatment of breast and ovarian cancer, but less than half of a leading candidate was 6-phosphofructo-2-kinase/fructose- these cancers respond to the drug. Enhancing the response to 2,6-bisphosphatase 2 (PFKFB2), an isoform of the glycolytic primary paclitaxel therapy could substantially improve out- enzyme phosphofructokinase 2 (PFK2). Analysis of this gene's comes for women with both diseases. Our group has found function in ovarian and breast cancers revealed that PFKFB2 that silencing several different glycolytic enzymes can enhance maintains intracellular redox balance, which attenuates paclitaxel sensitivity. The most significant enhancement of p53-dependent apoptotic cell death. Knockdown of PFKFB2 paclitaxel sensitivity has been observed by knocking down increased the glycolysis rate, but decreased the flow of inter- PFKFB2 in multiple ovarian and breast cancer cell lines and mediates through the PPP in cancer cells with wild-type TP53 xenografts that expressed wild-type TP53 (wtTP53). PFKFB2 is (wtTP53), decreasing NADPH. ROS accumulated after PFKFB2 a novel target to enhance paclitaxel-based primary chemo- knockdown, which stimulated Jun N-terminal kinase (JNK) therapy in ovarian cancers and breast cancers which retain and p53 phosphorylation, induced apoptosis that depended wtTP53. upon upregulation of p21 and Puma. Materials and Methods Cancer cells can exhibit enhanced glycolysis and lactate pro- Cell lines and cell culture duction even under normoxic conditions, that is, the Warburg Cell lines used in this article are listed in Supplementary Table effect (10, 11). Cancer cells often exhibit increased expression of S1. The identity of all cell lines was confirmed with short tandem glycolytic enzymes and glucose uptake, which result in markedly repeat DNA fingerprinting (December 18, 2018) in the MDACC enhanced glycolytic rates. In addition to producing additional Characterized Cell Line core (supported by NCI P30CA016672). ATP, increased glycolysis also generates three-carbon–building Cell line Mycoplasma test was performed using an ATCC PCR kit on blocks for the biosynthesis of proteins, lipids, and nucleic acids in November 20, 2018. rapidly growing cells (12). Many previous studies have shown that oncogenic signaling pathways regulate the activity of meta- Custom siRNA screen and data analysis bolic enzymes to support macromolecular synthesis in cancer A confirmatory screen with 12 positive hits (CKM, CKMT1B, cells, which is required for their rapid proliferation. Enzymes CKMT2, GCK, PDK3, PDK4, PFKFB2, PFKFB3, PFKFB4, PFKL, involved in altered glucose metabolism might provide important PFKM, and PGK10), which were selected from our initial screen, targets for cancer therapy (13, 14). The PPP consists of oxidative was conducted in four ovarian cancer (A2780, HeyA8, OC316, and nonoxidative branches. The oxidative branch is a major and OVCAR8) and two breast cancer (MCF-7 and ZR-75-1) cell source of reduced NADPH, a key reducing equivalent for lipid, lines. The same screening procedures were applied in the primary nucleotide, and aromatic amino acid biosynthesis (15). NADPH screen (23) and reagents used in the screen are listed in Supple- also plays a key role in maintaining intracellular redox homeo- mentary Table S2. stasis by maintaining a pool of reduced glutathione, which neutralizes reactive oxygen species (ROS). Cancer cells frequently Individual siRNA transfection have an increased burden of oxidative stress (16, 17) and are likely ON-TARGETplus PFKFB2 siRNA #6, #7, #8, and #9, TP53 to be more sensitive to the additional oxidative damage promoted siRNA #14, #15, and #16, SMARTpool
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