title: Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells.
abstract: OBJECTIVE
  The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis.
  
  
  METHODS
  H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor.
  
  
  RESULTS
  Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation.
  
  
  CONCLUSIONS
  The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.
authors.affiliation: Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232-5671, USA.
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Sun
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.forename: Artour
authors.initials: A
authors.lastname: Torossian
authors.forename: Christina K
authors.initials: CK
authors.lastname: Speirs
authors.forename: Stephen
authors.initials: S
authors.lastname: Schleicher
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Giacalone
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
mesh_terms: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D010455:Peptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D000444:Aldehyde Dehydrogenase; D017526:Receptor, IGF Type 1; D002945:Cisplatin