Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival

被引:162
作者
Ros, Susana [1 ]
Santos, Claudio R. [1 ]
Moco, Sofia [4 ]
Baenke, Franziska [1 ]
Kelly, Gavin [2 ]
Howell, Michael [3 ]
Zamboni, Nicola [4 ]
Schulze, Almut [1 ]
机构
[1] Canc Res UK London Res Inst, Gene Express Anal Lab, London WC2A 3LY, England
[2] Canc Res UK London Res Inst, Bioinformat & Biostat Serv, London WC2A 3LY, England
[3] Canc Res UK London Res Inst, High Throughput Screening Facil, London WC2A 3LY, England
[4] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland
关键词
FATTY-ACID SYNTHASE; LKB1-AMPK PATHWAY; PYRUVATE-KINASE; EXPRESSION; GENE; INHIBITION; GROWTH; FRUCTOSE-6-PHOSPHATE; GLYCOLYSIS; OVEREXPRESSION;
D O I
10.1158/2159-8290.CD-11-0234
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial cell line. This approach revealed significant complexity in the metabolic requirements of prostate cancer cells and identified several genes selectively required for their survival. Among these genes was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), an isoform of phosphofructokinase 2 (PFK2). We show that PFKFB4 is required to balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells. Depletion of PFKFB4 inhibited tumor growth in a xenograft model, indicating that it is required under physiologic nutrient levels. PFKFB4 mRNA expression was also found to be greater in metastatic prostate cancer compared with primary tumors. Taken together, these results indicate that PFKFB4 is a potential target for the development of antineoplastic agents. SIGNIFICANCE: Cancer cells undergo several changes in their metabolism that promote growth and survival. Using an unbiased functional screen, we found that the glycolytic enzyme PFKFB4 is essential for prostate cancer cell survival by maintaining the balance between the use of glucose for energy generation and the synthesis of antioxidants. Targeting PFKFB4 may therefore present new therapeutic opportunities. Cancer Discov; 2(4); 328-43. (c) 2012 AACR.
引用
收藏
页码:328 / 343
页数:16
相关论文
共 50 条
[1]   Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses [J].
Anastasiou, Dimitrios ;
Poulogiannis, George ;
Asara, John M. ;
Boxer, Matthew B. ;
Jiang, Jian-kang ;
Shen, Min ;
Bellinger, Gary ;
Sasaki, Atsuo T. ;
Locasale, Jason W. ;
Auld, Douglas S. ;
Thomas, Craig J. ;
Vander Heiden, Matthew G. ;
Cantley, Lewis C. .
SCIENCE, 2011, 334 (6060) :1278-1283
[2]  
Atsumi T, 2002, CANCER RES, V62, P5881
[3]   Chemical inhibition of Acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells [J].
Beckers, Annelies ;
Organe, Sophie ;
Tinunermans, Leen ;
Scheys, Katryn ;
Peeters, Annelies ;
Brusselmans, Koen ;
Verhoeven, Guido ;
Swinnen, Johannes V. .
CANCER RESEARCH, 2007, 67 (17) :8180-8187
[4]   Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18 [J].
Bello, D ;
Webber, MM ;
Kleinman, HK ;
Wartinger, DD ;
Rhim, JS .
CARCINOGENESIS, 1997, 18 (06) :1215-1223
[5]   TIGAR, a p53-inducible regulator of glycolysis and apoptosis [J].
Bensaad, Karim ;
Tsuruta, Atsushi ;
Selak, Mary A. ;
Calvo Vidal, M. Nieves ;
Nakano, Katsunori ;
Bartrons, Ramon ;
Gottlieb, Eyal ;
Vousden, Karen H. .
CELL, 2006, 126 (01) :107-120
[6]   Modulation of intracellular ROS levels by TIGAR controls autophagy [J].
Bensaad, Karim ;
Cheung, Eric C. ;
Vousden, Karen H. .
EMBO JOURNAL, 2009, 28 (19) :3015-3026
[7]   Statistical methods for analysis of high-throughput RNA interference screens [J].
Birmingham, Amanda ;
Selfors, Laura M. ;
Forster, Thorsten ;
Wrobel, David ;
Kennedy, Caleb J. ;
Shanks, Emma ;
Santoyo-Lopez, Javier ;
Dunican, Dara J. ;
Long, Aideen ;
Kelleher, Dermot ;
Smith, Queta ;
Beijersbergen, Roderick L. ;
Ghazal, Peter ;
Shamu, Caroline E. .
NATURE METHODS, 2009, 6 (08) :569-575
[8]   Hypoxic regulation of PFYFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFYFB genes in gastric cancers [J].
Bobarykina, Anastasiya Y. ;
Minchenko, Dmytro O. ;
Opentanova, Iryna L. ;
Moenner, Michel ;
Caro, Jaime ;
Esumi, Hiroyasu ;
Minchenko, Oleksandr H. .
ACTA BIOCHIMICA POLONICA, 2006, 53 (04) :789-799
[9]   Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry Method for Fast and Robust Quantification of Anionic and Aromatic Metabolites [J].
Buescher, Joerg Martin ;
Moco, Sofia ;
Sauer, Uwe ;
Zamboni, Nicola .
ANALYTICAL CHEMISTRY, 2010, 82 (11) :4403-4412
[10]   Cross-Platform Comparison of Methods for Quantitative Metabolomics of Primary Metabolism [J].
Buescher, Joerg Martin ;
Czernik, Dominika ;
Ewald, Jennifer Christina ;
Sauer, Uwe ;
Zamboni, Nicola .
ANALYTICAL CHEMISTRY, 2009, 81 (06) :2135-2143