title: Role of p53, Bax, p21, and DNA-PKcs in radiation sensitivity of HCT-116 cells and xenografts.
abstract: BACKGROUND
  Molecular factors that dictate tumor response to ionizing radiation in rectal cancer are not well described.
  
  
  METHODS
  We investigated the contribution of p53, p21, Bax, and DNA-PKcs in response to ionizing radiation in an isogeneic colorectal cancer system in vitro and in vivo.
  
  
  RESULTS
  HCT-116 DNA-PKcs(-/-) cells and xenografts were radiosensitive compared with wild-type (WT) HCT-116 cells. HCT-116 p53(-/-) cells and tumor xenografts displayed a radioresistant phenotype. Separately, p21 or Bax deficiency was associated with a radiosensitive phenotype in vitro and in vivo. In vivo, Bax deficiency led to increased tumor necrosis and decreased microvessel density. In vitro, HCT-116 Bax(-/-) cells had decreased levels of vascular endothelial growth factor. HCT-116 WT cells had a more radioresistant phenotype after pancaspase inhibition, but pancaspase inhibition did not alter radiosensitivity in HCT-116 Bax(-/-) cells subjected to ionizing radiation. There was no difference in cell growth in HCT-116 WT cells subjected to transient apoptosis-inducing factor (AIF) inhibition; however, HCT-116 Bax(-/-) cells treated with AIF siRNA followed by ionizing radiation had a significant survival advantage compared with control-treated cells, implicating AIF in the radiosensitivity of Bax(-/-) cells.
  
  
  CONCLUSIONS
  These data might be used along with other markers to predict response to radiation in patients with rectal cancer.
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center and North Texas VA Health Care System, Dallas, Texas 75216, USA. Sergio.Huerta@UTSouthwestern.edu
authors.forename: Sergio
authors.initials: S
authors.lastname: Huerta
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Gao
authors.forename: Sean
authors.initials: S
authors.lastname: Dineen
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Debrabata
authors.initials: D
authors.lastname: Saha
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Meyer
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000502:physiology; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D011836:Radiation Tolerance; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000502:physiology*
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051747:DNA-Activated Protein Kinase