title: Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.
abstract: BACKGROUND
  Effective treatment of prostate cancer should be based on targeting interactions between tumour cell signalling pathways and key converging downstream effectors. Here, we determined how the tumourigenic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), tumour-suppressive phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and transforming growth factor-β (TGF-β) pathways are integrated via the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1). Moreover, we assessed how the novel anti-tumour agent, Dp44mT, may target these integrated pathways by increasing NDRG1 expression.
  
  
  METHODS
  Protein expression in Dp44mT-treated normal human prostate epithelial cells and prostate cancer cells (PC-3, DU145) was assessed by western blotting. The role of NDRG1 was examined by transfection using an NDRG1 overexpression vector or shRNA.
  
  
  RESULTS
  Dp44mT increased levels of tumour-suppressive PTEN, and decreased phosphorylation of ERK1/2 and SMAD2L, which are regulated by oncogenic Ras/MAPK signalling. Importantly, the effects of Dp44mT on NDRG1 and p-SMAD2L expression were more marked in prostate cancer cells than normal prostate epithelial cells. This may partly explain the anti-tumour selectivity of these agents. Silencing NDRG1 expression increased phosphorylation of tumourigenic AKT, ERK1/2 and SMAD2L and decreased PTEN levels, whereas NDRG1 overexpression induced the opposite effect. Furthermore, NDRG1 silencing significantly reduced the ability of Dp44mT to suppress p-SMAD2L and p-ERK1/2 levels.
  
  
  CONCLUSIONS
  NDRG1 has an important role in mediating the tumour-suppressive effects of Dp44mT in prostate cancer via selective targeting of the PI3K/AKT, TGF-β and ERK pathways.
authors.affiliation: Department of Pathology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: K M
authors.initials: KM
authors.lastname: Dixon
authors.forename: G Y L
authors.initials: GY
authors.lastname: Lui
authors.forename: Z
authors.initials: Z
authors.lastname: Kovacevic
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Yao
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
authors.forename: S J
authors.initials: SJ
authors.lastname: Assinder
authors.forename: D R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D013882:Thiosemicarbazones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D013882:Thiosemicarbazones; D016212:Transforming Growth Factor beta; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497782:SMAD2 protein, human; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; C494929:PTEN protein, human