title: Chemopreventive and chemotherapeutic actions of mTOR inhibitor in genetically defined head and neck squamous cell carcinoma mouse model.
abstract: OBJECTIVE
  To assess the efficacy of rapamycin treatment in chemoprevention and chemotherapy of tumorigenesis in a genetically defined mouse model of head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  Knockdown of Tgfbr1 and/or Pten using siRNA-mediated RNA interference was carried out in human HNSCC cell lines to analyze molecular changes in the mTOR pathway. Tgfbr1(flox/flox); Pten(flox/flox); K14-CreER(tam) mice were treated with oral gavage of tamoxifen for the conditional deletion of Tgfbr1 and Pten in oral mucosa, resulting in HNSCC. Tgfbr1 and Pten conditonal deletion (2cKO) mice were treated with rapamycin before or after the onset of HNSCC, and the efficacy of this treatment was assessed by determining tumor burden, longevity, and molecular analysis of the mTOR pathway. Molecular changes observed in human HNSCC cell lines and 2cKO mice were compared to identify key alterations in the mTOR pathway.
  
  
  RESULTS
  Knockdown of Tgfbr1 and/or Pten in human HNSCC cell lines resulted in activation of mTOR activity complex 1 and increased levels of survivin. Furthermore, we observed similar changes in HNSCC of the 2cKO mouse. In the human HNSCC tissue array, a loss of Tgfbr1 expression correlated with increased survivin levels. Chemopreventive rapamycin treatment significantly delayed the onset of the HNSCC tumors and prolonged survival in 2cKO mice. In addition, we also found that rapamycin had a therapeutic effect on squamous cell carcinomas in these mice. In 2cKO HNSCC tongue tumors, rapamycin treatment induced apoptosis, inhibited cell proliferation and phosphorylation of Akt and S6, and decreased survivin expression.
  
  
  CONCLUSIONS
  These findings indicate that tumorigenesis in 2cKO HNSCC is associated with activation of the Akt/mTOR/survivin pathway, and inhibition of this pathway by rapamycin treatment successfully ameliorates the onset and progression of tumorigenesis.
authors.affiliation: National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Sun
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Bradford
authors.initials: B
authors.lastname: Hall
authors.forename: Yansong
authors.initials: Y
authors.lastname: Bian
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage*; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D018125:Receptors, Transforming Growth Factor beta; D000077022:Survivin; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus