title: Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel.
abstract: BACKGROUND
  The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments.
  
  
  OBJECTIVE
  The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel.
  
  
  METHODS
  DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT-PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting.
  
  
  RESULTS
  The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel.
  
  
  CONCLUSIONS
  The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.
authors.affiliation: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, Learning and Research Building, Southmead Hospital, Bristol, UK.
authors.forename: C C
authors.initials: CC
authors.lastname: Uzoh
authors.forename: J M P
authors.initials: JM
authors.lastname: Holly
authors.forename: K M
authors.initials: KM
authors.lastname: Biernacka
authors.forename: R A
authors.initials: RA
authors.lastname: Persad
authors.forename: A
authors.initials: A
authors.lastname: Bahl
authors.forename: D
authors.initials: D
authors.lastname: Gillatt
authors.forename: C M
authors.initials: CM
authors.lastname: Perks
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D018971:Insulin-Like Growth Factor Binding Protein 2; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D043823:Taxoids; D000077143:Docetaxel; D007334:Insulin-Like Growth Factor I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human