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The ataxia telangiectasia group D associated gene confers a cellular survival advantage in pancreatic adenocarcinoma

Journal of Surgical Research
Publication Date
DOI: 10.1016/j.jss.2003.08.131
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Abstract Introduction: Recently we have determined that the gene Ataxia-Telangiectasia Group D Associated (ATDC) is significantly over- expressed in >90% of human pancreatic adenocarcinomas. The role of ATDC in tumorigenesis is unknown. We hypothesize that ATDC promotes growth and confers survival advantage after radiation exposure in pancreatic cancer. Methods: To examine the role of ATDC in pancreatic cancer, we designed an anti-ATDC small inhibitory RNA (siRNA) as well as a mutated anti-ATDC siRNA (msiRNA) to serve as a control. Stable expression of both the anti-ATDC siRNA and the msiRNA was established in BxPC-3 cells, a pancreatic cancer cell line with high endogenous ATDC expression. ATDC expression was assessed by Western blotting. Cell growth was calculated by counting cell number. Following exposure to ionizing radiation (0–10 gy), the surviving fraction of cells after 2 weeks was analyzed by clonigenic assay. The effect of radiation exposure (5 gy) on cell cycle distribution was assessed by FACS analysis of propidium iodide stained cells. Results: Silencing of ATDC was confirmed by Western blotting in BxPC-3 cells expressing anti-ATDC siRNA, while the control msiRNA had little effect. Cellular proliferation in ATDC silenced cells was significantly inhibited compared to msiRNA and WT cells (fold change compared to time 0: siRNA = 0.97 ± 0.29∗, msiRNA = 2.92 ± 0.43, WT = 4.19 ± 0.79, ∗p < 0.05 vs. WT and msiRNA at 96 hours). Clonigenic assays revealed that following exposure to ionizing radiation, BxPC-3 cells with silenced ATDC were more sensitive to the effects of ionizing radiation than control cells (radiation dose for 1% survival: WT = 11.60 ± 0.06 gy; siRNA = 10.16 ± 0.70 gy). Preliminary analysis of cell cycle distribution 12 hours after exposure to 5 gy ionizing radiation showed an increased S phase fraction in ATDC silenced cells compared to msiRNA and WT (siRNA = 37.2%, msiRNA = 3.2%, WT = 3.5%), suggesting a role for ATDC in repair of DNA damage. Conclusion: Silencing of ATDC expression in BxPC-3 cells leads to decreased growth rate and increased sensitivity to ionizing radiation. Our data indicate that ATDC may be a therapeutic target in pancreatic cancer by inhibiting tumor growth and increasing sensitivity to radiation therapy.

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