title: Expression of metabolically targeted biomarkers in endometrial carcinoma.
abstract: OBJECTIVE
  The differential metabolic phenotype observed between malignant and non-transformed cells may constitute a biochemical basis for therapeutic intervention. Increased glucose uptake is one of the major metabolic changes found in malignant tumors, a process that is mediated by glucose transporters such as Glut1. Cellular growth can be regulated by mTOR in response to the nutrient milieu. In this study, we sought to determine if endometrial carcinoma cells express Glut1 and mTOR, and if inhibition of these factors is cytotoxic to endometrial carcinoma cells in vitro.
  
  
  METHODS
  Expression of Glut1, pAkt, and pmTOR was assessed in tissue microarrays constructed from 42 type I and 34 type II endometrial tumors by immunohistochemistry, and in a panel of endometrial carcinoma cell lines. Representative endometrial carcinoma cells with wild type or mutant endogenous PTEN were treated with the glucose analog 2-deoxyglucose (2-DG) and rapamycin, an mTOR inhibitor or cisplatin. Inhibition of cell growth and mechanism of cell death was determined.
  
  
  RESULTS
  Glut1, pAkt, and pmTOR were expressed strongly in both types I and II endometrial carcinoma. 2-DG and rapamycin induced apoptotic cell death in type I endometrial carcinoma cells, and profound growth inhibition and cytostasis in type II endometrial carcinoma cells.
  
  
  CONCLUSIONS
  Glut1, pAkt, and pmTOR are overexpressed in endometrial carcinomas. Distinct alterations in the phosphatidylinositol 3'-kinase (PI3K) pathway upstream of mTOR, such as pAkt, may identify endometrial carcinoma patients who may benefit from adjuvant treatment with mTOR inhibitors and/or glucose analogs.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Wahl
authors.forename: Sayeema
authors.initials: S
authors.lastname: Daudi
authors.forename: Malti
authors.initials: M
authors.lastname: Kshirsagar
authors.forename: Kent
authors.initials: K
authors.lastname: Griffith
authors.forename: Lijun
authors.initials: L
authors.lastname: Tan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rhode
authors.forename: J Rebecca
authors.initials: JR
authors.lastname: Liu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D016503:Drug Delivery Systems; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D003847:Deoxyglucose; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus