title: Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Susana
authors.initials: S
authors.lastname: Ros
authors.forename: Claudio R
authors.initials: CR
authors.lastname: Santos
authors.forename: Sofia
authors.initials: S
authors.lastname: Moco
authors.forename: Franziska
authors.initials: F
authors.lastname: Baenke
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.forename: Almut
authors.initials: A
authors.lastname: Schulze
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006019:Glycolysis; D006801:Humans; D008297:Male; D055432:Metabolomics; D010084:Oxidation-Reduction; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics
chemical_list: C506672:PFKFB4 protein, human; D034741:RNA, Small Interfering; D025481:Phosphofructokinase-2; C526182:PRKAB1 protein, human; D055372:AMP-Activated Protein Kinases