Induction and loss of a TP53-dependent radioadaptive response in the human lymphoblastoid cell model TK6 and its abrogation by BCL2 over-expression.

Purpose: 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.

Materials And 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.

Conclusion: 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.