Speaker
Dr
Nina F. Jeppesen Edin
(University of Oslo)
Description
We have previously found that protracting a priming dose of 0.3 Gy over 1 hour resulted in permanent elimination of low dose hyper radio-sensitivity (HRS) instead of the transient elimination by an acute priming with the same dose. The cells exposed to the low dose-rate priming secreted a factor into the medium, which removed HRS transiently in recipient cells. The factor could also be induced by low dose-rate irradiation of cell conditioned medium but only when serum was present in the medium during conditioning.
We have now identified the serum factor as interleukin-13 and the factor secreted by the low dose-rate primed cells as TGFβ3 and propose a model for a self-sustaining molecular mechanism responsible for permanent elimination HRS transmitted to the progeny.
Two cell lines known to display HRS were used, T-47D breast cancer cells and T98G glioblastoma cells. The change to a HRS-negative phenotype was found to be transiently induced by extracellular TGFβ3, which could be activated through iNOS activity by low dose-rate irradiation (0.2-0.3 Gy/h for 1 h) of cell conditioned medium. However, direct cell irradiation at low dose-rate induced a permanent elimination of HRS by activation of a self-sustaining mechanism found to depend on iNOS activity and resulting in continuously elevated cytoplasmic levels of TGFβ3. The HRS-negative phenotypes of T-47D and T98G were reversed by iNOS inhibitor 1400W. Interestingly, HRS was induced by 1400W in the HRS-negative cervix cancer cell line NHIK 3025. The effect of low dose-rate irradiation could be mimicked by high dose-rate irradiation or reoxygenation after hypoxia in combination with NO.
The data show how resistance against low levels of DNA-damage can be turned on (by TGFβ3) or off (by iNOS inhibition) in cells. In addition, the data contributes to the understanding of the importance of distinguishing between dose-rates in relation to radiation protection issues and indicate that the effects induced by low dose-rate irradiation are related to NO production and independent of DNA-damage.
Preliminary results confirm the findings in a mouse model.
Primary author
Dr
Nina F. Jeppesen Edin
(University of Oslo)
Co-authors
Prof.
Agnes Görlach
(German Heart Center Munich)
Mr
Cheng Chang
(University of Oslo)
Prof.
Erik Pettersen
(University of Oslo)
Ms
Hilde S. Vollan
(University of Oslo)
Mr
Joe Sandvik
(University of Oslo)
Ms
Katharina Reger
(German Heart Center Munich)
Prof.
Linda Bergersen
(University of Oslo)
