title: Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways.
abstract: OBJECTIVE
  Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities.
  
  
  METHODS
  Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers.
  
  
  RESULTS
  Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing-induced apoptosis. K-Ras-mutated, c-Met-amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing-induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways.
  
  
  CONCLUSIONS
  Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways.
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.forename: Ka-Kui
authors.initials: KK
authors.lastname: Chan
authors.forename: Claire
authors.initials: C
authors.lastname: Grills
authors.forename: James T
authors.initials: JT
authors.lastname: Murray
authors.forename: Angela
authors.initials: A
authors.lastname: Platt-Higgins
authors.forename: Osama Sharaf
authors.initials: OS
authors.lastname: Eldin
authors.forename: Ken
authors.initials: K
authors.lastname: O'Byrne
authors.forename: Pasi
authors.initials: P
authors.lastname: Janne
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rudland
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Tanani
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046912:Multiprotein Complexes; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009361:Neoplasm Invasiveness; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D020928:Mitogen-Activated Protein Kinases; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D053495:Osteopontin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; D020931:ran GTP-Binding Protein; D018631:ras Proteins; C117307:KRAS protein, human; C120587:RAN protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human
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