Abstract 4759: TP53 control of the survivin-mediated radio-adaptive response in human tumors

Abstract

Abstract Doses of ionizing radiation ≤100 mGy induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to doses as low as 5 mGy and is controlled by p53 expression. Experiments were performed using ten human cancer cell lines: HCT116 TP53 wild type (WT) colorectal carcinoma and its isogenic TP53 null mutant (Mut); RKO colorectal carcinoma TP53 WT and associated isogenic TP53 null Mut; breast adenocarcinomas MCF7 (TP53 WT) and MDA-MB-231 (TP53 Mut); lung carcinomas A549 (TP53 WT) and NCI-H1975 (TP53 Mut); and pancreatic carcinomas Hs766T (TP53 WT) and Panc-1 (TP53 Mut). Doses of 5 mGy were used to induce changes in the response of these tumor cells to higher therapy doses using a multi-dosing paradigm. Effects on radiation sensitivity were associated with changes in both survivin concentration and its translocation to the cytoplasm (TP53 WT) and nucleus (TP53 null or point mutant). In vitro survival (2 Gy per fraction, two once daily fractions) studies were performed on all tumor cell lines. Intracellular localization of survivin was determined by ELISA and correlated to survival response. 2 Gy alone had no significant effect on intracellular translocation of survivin. When preceded 15 min earlier by a 5 mGy exposure, survivin increased in the cytoplasm of all TP53 WT tumor cell lines as compared to the nuclei of their counterpart isogenic TP53 null lines (HCT116 and RKO) or those carrying TP53 point mutations (MDA-MB-231, NCI-H1975, Panc-1). All TP53 WT tumor lines were significantly protected P < 0.001 by the addition of a 5 mGy dose while TP53 Mut lines, isogenic null or point mutated, were sensitized P < 0.001. HCT116 and RKO TP53 WT cells were admixed and grown with their respective isogenic TP53 null counterpart at ratios of 1:3, 1:1, and 3:1. Under each of these growth conditions, the mixed cultures expressed an enhanced sensitization (P ≤ 0.035) characteristic of that expressed by cultures of 100% TP53 Mut tumor cells suggesting cell to cell communication and/or a diffusible factor(s) affected by TP53 Mut cells is playing an important role in the expression of this survivin-mediated radio-adaptive response. We have identified a very low radiation dose-induced survivin-mediated radio-adaptive response whose expression is linked to TP53 mutational status that could affect therapeutic outcomes associated with the routine usage of imaging procedures in conventional radiation therapy. This work was supported in part by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.) Citation Format: Jeffrey S. Murley, Richard C. Miller, Ralph R. Weichselbaum, David J. Grdina. TP53 control of the survivin-mediated radio-adaptive response in human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4759. doi:10.1158/1538-7445.AM2017-4759