title: The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma.
abstract: OBJECTIVE
  To validate the overexpression of insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) in low-grade serous ovarian carcinoma (SOC), and to investigate whether the IGF-1 pathway is a potential therapeutic target for low-grade SOC.
  
  
  METHODS
  Gene expression profiling was performed on serous borderline ovarian tumors (SBOTs) and low-grade SOC, and overexpression of IGF-1 in low-grade SOC was validated by RT-PCR and immunohistochemistry. The effect of exogenous IGF-1 on cell proliferation was determined in cell lines by cell proliferation assays, cell migration assays, and Western blot. Signaling pathways downstream of IGF-1 and the effects of the AKT inhibitor MK-2206 were investigated by Western blot analysis and by generating IGF-1R short hairpin RNA stable knockdown cell lines. Low- and high-grade cell lines were treated with the dual IGF-1R- and insulin receptor-directed tyrosine kinase inhibitor OSI-906, and cellular proliferation was measured.
  
  
  RESULTS
  mRNA analysis and immunostaining revealed significantly higher IGF-1 expression in low-grade SOCs than in SBOTs or high-grade SOCs. In response to exogenous treatment with IGF-1, low-grade cell lines exhibited more intense upregulation of phosphorylated AKT than did high-grade cell lines, an effect that was diminished with IGF-1R knockdown and MK-2206 treatment. Low-grade SOC cell lines were more sensitive to growth inhibition with OSI-906 than were high-grade cell lines.
  
  
  CONCLUSIONS
  IGF-1 is overexpressed in low-grade SOCs compared with SBOTs and high-grade SOCs. Additionally, low-grade SOC cell lines were more responsive to IGF-1 stimulation and IGF-1R inhibition than were high-grade lines. The IGF-1 pathway is therefore a potential therapeutic target in low-grade SOC.
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. erking@mdanderson.org
authors: Erin R
authors: ER
authors: King
authors: Zhifei
authors: Z
authors: Zu
authors: Yvonne T M
authors: YT
authors: Tsang
authors: Michael T
authors: MT
authors: Deavers
authors: Anais
authors: A
authors: Malpica
authors: Samuel C
authors: SC
authors: Mok
authors: David M
authors: DM
authors: Gershenson
authors: Kwong-Kwok
authors: KK
authors: Wong
mesh_terms: D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; C548887:MK 2206; D011719:Pyrazines; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt