Role of p53, Bax, p21, and DNA-PKcs in radiation sensitivity of HCT-116 cells and xenografts

Surgery. 2013 Aug;154(2):143-51. doi: 10.1016/j.surg.2013.03.012.

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.

Conclusion: These data might be used along with other markers to predict response to radiation in patients with rectal cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Inducing Factor / physiology
  • Colorectal Neoplasms / radiotherapy*
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology*
  • DNA-Activated Protein Kinase / physiology*
  • HCT116 Cells
  • Humans
  • Mice
  • Radiation Tolerance*
  • Tumor Suppressor Protein p53 / physiology*
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein / physiology*

Substances

  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • BAX protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • DNA-Activated Protein Kinase