Induction and loss of a TP53-dependent radioadaptive response in the human lymphoblastoid cell model TK6 and its abrogation by BCL2 over-expression.
OBJECTIVE
To characterize the radioadaptive response in the human lymphoblastoid cell model TK6, and determine: (i) Whether repeated low dose exposures are more effective than single acute exposures in inducing resistance, (ii) the time-course for induction and loss of resistance following chronic exposures, and (iii) the effect of TP53 deletion or BCL2 over-expression on the induction of an adaptive response.


METHODS
TK6, a human B-lymphoblastoid cell line, TK6-BCL2, a TK6 line that over-expresses BCL2 and is resistant to radiation-induced apoptosis, and NH32, a TP53 knockout of TK6 that is also resistant to apoptosis were studied. Cells were exposed to chronic, daily doses of 10 cGy given over 1 -21 days before being challenged with 1 -5 Gy exposures. Cell survival and chromatid break induction following high dose challenge were used to evaluate adaptive radiation responses.


RESULTS
Exposure to 10 cGy gamma rays induced resistance to killing and chromosome break induction in TK6 cells, but not in either TK6-BCL2 or NH32 cells. Resistance in TK6 was observed 4 h after exposure, and cells remained resistant for about 48 h. Maximal resistance was induced by a single 10 cGy dose. Repeated 10 cGy exposures had no additional effect on radiation sensitivity, except to maintain the induced radioresistance.


CONCLUSIONS
An adaptive response is maximally and rapidly induced by a single low dose exposure in TK6 cells, and it has a limited lifespan. Induction of an adaptive response in TK6 cells can be abrogated by either TP53 loss or BCL2 over-expression. The characteristics of induced resistance in TK6 cells suggest that alterations in TP53-dependent apoptotic responses may be one mechanism for resistance.
Schwartz
Jeffrey L
JL
University of Washington, USA. jschwart@uwashington.edu
Jordan
Robert
R
Slovic
Jana
J
Moruzzi
Audrey M
AM
Kimmel
Robert R
RR
Liber
Howard L
HL
D000222:Adaptation, Physiological / Q000528:radiation effects; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D015870:Gene Expression / Q000528:radiation effects*; D006801:Humans; D009154:Mutation / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53