title: Key role of phosphoinositide 3-kinase class IB in pancreatic cancer.
abstract: OBJECTIVE
  Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110α isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells.
  
  
  METHODS
  The expression of all PI3K isoforms and downstream targets was analyzed by immunohistochemistry in human pancreatic cancer tissue and normal counterparts. Isoform selective inhibitors and short interfering RNA (siRNA) were employed to investigate the effects of the different PI3Ks on proliferation, survival, and intracellular signaling in PDAC cell lines.
  
  
  RESULTS
  Immunohistochemical screening revealed high specific expression of the PI3K/p110γ isoform. Scoring indicated that 72% of the PDAC tissue stained positive for PI3K/p110γ, whereas no stain was detected in normal pancreatic ducts. Proliferation analyses after selective inhibition and siRNA downregulation of PI3K/p110γ showed that PI3K/p110γ, but not other PI3K isoforms, was required for cell proliferation. Overexpression of PI3K/p110γ indeed increased cell numbers and mediated activation of Akt in PDAC cell lines. Moreover, PI3K/p110γ was required for Akt activation via lysophosphatidic acid receptors.
  
  
  CONCLUSIONS
  These data represent the first identification of a tumor-specific accumulation of the PI3K isoform p110γ in human cancer. Further, our results signify a critical role for PI3K/p110γ in pancreatic cancer, and we hypothesize that PI3K/p110γ overexpression is a key event in the disease progression.
authors.affiliation: Inositide Signalling Group, Centre for Diabetes, Blizard Institute of Cell and Molecular Science, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Edling
authors.forename: Federico
authors.initials: F
authors.lastname: Selvaggi
authors.forename: Richard
authors.initials: R
authors.lastname: Buus
authors.forename: Tania
authors.initials: T
authors.lastname: Maffucci
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Di Sebastiano
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Paolo
authors.initials: P
authors.lastname: Innocenti
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection
chemical_list: C512438:5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt