Inactivation of gadd45a sensitizes epithelial cancer cells to ionizing radiation in vivo resulting in prolonged survival.
Ionizing radiation (IR) therapy is one of the most commonly used treatments for cancer patients. The responses of tumor cells to IR are often tissue specific and depend on pathway aberrations present in the tumor. Identifying molecules and mechanisms that sensitize tumor cells to IR provides new potential therapeutic strategies for cancer treatment. In this study, we used two genetically engineered mouse carcinoma models, brain choroid plexus carcinoma (CPC) and prostate, to test the effect of inactivating gadd45a, a DNA damage response p53 target gene, on tumor responses to IR. We show that gadd45a deficiency significantly increases tumor cell death after radiation. Effect on survival was assessed in the CPC model and was extended in IR-treated mice with gadd45a deficiency compared with those expressing wild-type gadd45a. These studies show a significant effect of gadd45a inactivation in sensitizing tumor cells to IR, implicating gadd45a as a potential drug target in radiotherapy management.
Lu
Xiangdong
X
Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Yang
Chunyu
C
Hill
Reginald
R
Yin
Chaoyin
C
Hollander
M Christine
MC
Fornace
Albert J
AJ
Van Dyke
Terry
T
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology*; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011839:Radiation, Ionizing; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins