title: Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy.
abstract: BACKGROUND
  We have shown that an Akt inhibitor, MK2206, reduces hepatocellular carcinoma (HCC) proliferation. To further delineate MK2206, we sought to investigate the Notch1 pathway and hypothesize that MK2206 treatment will result in Notch1 inhibition with either subsequent or parallel Akt suppression.
  
  
  METHODS
  HCC cell lines were treated with various concentrations of MK2206. Cell proliferation was determined via real-time live cell imaging. Knockdown of Notch1 was used to observe interaction between Notch1 and pAkt. Cell lysates were analyzed via Western blotting for Notch and Akt pathway targets.
  
  
  RESULTS
  After treatment with MK2206 (up to 2 μM), there was a 60% reduction in cell viability at 48 hours with a concomitant reduction in Notch1 expression. Knockdown of Notch1 in HCC cell lines correlated with reduction in Akt phosphorylation.
  
  
  CONCLUSIONS
  MK2206 inhibits both the PI3-K/Akt and Notch1 pathways. Therefore, further characterization of MK2206 comparing the 2 pathways is warranted and the effect of dual targeting in HCC.
authors: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Kevin M
authors: KM
authors: Sokolowski
authors: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Mariappan
authors: M
authors: Balamurugan
authors: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Selvi
authors: S
authors: Kunnimalaiyaan
authors: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Jacob
authors: J
authors: Wilson
authors: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: tcgamblin@mcw.edu.
authors: Thomas Clark
authors: TC
authors: Gamblin
authors: Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: mkunnima@mcw.edu.
authors: Muthusamy
authors: M
authors: Kunnimalaiyaan
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D051881:Receptor, Notch1; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Dual target; Hepatocellular carcinoma; MK2206; Notch