title: Dependence on PI3K/Akt signaling for malignant rhabdoid tumor cell survival.
abstract: OBJECTIVE
  Malignant rhabdoid tumors (MRT), although rare, are one of the most aggressive pediatric malignancies. Loss of INI1, a tumor suppressor gene and member of the SWI/SNF chromatin remodeling complex, is a recurrent genetic characteristic of these tumors and an important diagnostic marker. We have previously demonstrated a novel interaction between the serine/threonine kinase Akt and INI1, as well as other SWI/SNF subunits. This, coupled with experiments in the literature suggesting that the PI3K/Akt pathway is dysregulated in MRT cells, caused us to investigate the activation and importance of this pathway in this tumor type.
  
  
  METHODS
  In this study, we used MTT assays to evaluate the sensitivity of MRT cell lines to PI3K inhibition. Western blot analysis and Raf pulldown assays were used to examine potential mechanisms of PI3K/Akt dysregulation.
  
  
  RESULTS
  Inhibition of the PI3K/Akt pathway caused a significant reduction in the survival of the four MRT cell lines tested, and three cell lines demonstrated constitutively active Akt. Two of these constitutively active Akt cell lines abundantly expressed IGF-1R and an inhibitor of IGF-1R, NVP-AEW541, reduced Akt phosphorylation in one of them. The third constitutively active Akt cell line appeared to express a mutant IGF-1R.
  
  
  CONCLUSIONS
  Our data suggests that the PI3K/Akt pathway is a crucial means of maintaining the survival and growth of MRT cells. The cells therefore employ various mechanisms to stimulate this pathway, and growth factor receptor dysregulation appears to be a common method. Drugs that inhibit the PI3K pathway or interfere with IGF autocrine loops may be of great value in treating MRT, which is largely resistant to conventional chemotherapeutic approaches.
authors.affiliation: Pathology and Laboratory, Medical University of South Carolina, Charleston, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Foster
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wright
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1; D018631:ras Proteins; C501177:NVP-AEW541