TY - JOUR
T1 - Role of p53, Bax, p21, and DNA-PKcs in radiation sensitivity of HCT-116 cells and xenografts
AU - Huerta, Sergio
AU - Gao, Xiaohuan
AU - Dineen, Sean
AU - Kapur, Payal
AU - Saha, Debrabata
AU - Meyer, Jeffrey
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84880867961&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880867961&partnerID=8YFLogxK
U2 - 10.1016/j.surg.2013.03.012
DO - 10.1016/j.surg.2013.03.012
M3 - Article
C2 - 23889944
AN - SCOPUS:84880867961
VL - 154
SP - 143
EP - 151
JO - Surgery
JF - Surgery
SN - 0039-6060
IS - 2
ER -