Insulin and Insulin-Like Growth Factor-1 (IGF-1) Inhibit Repair of Potentially Lethal Radiation Damage and Chromosome Aberrations and Alter DNA Repair Kinetics in Plateau-Phase A549 Cells

Abstract

Plateau-phase A549 cells exhibit a high capacity for repair of potentially lethal radiation damage (PLD) when allowed to recover in their own spent medium. Addition of either insulin or insulin-like growth factor-1 (IGF-1) to the spent medium 60 to 120 min before irradiation significantly inhibits PLD repair. The 9-h recovery factor (survival with holding/survival without holding) is reduced from 10.8 +/- 0.7 to 3.4 +/- 0.3 by insulin and to 3.0 +/- 0.4 by IGF-1. Neither growth factor alters the cell age distribution of the plateau-phase cells, increases the rate of incorporation of 5-bromo-2'-deoxyuridine into DNA, or alters the extent of radiation-induced mitotic delay in cells subcultured immediately after irradiation. Both insulin and IGF-1 alter the kinetics for rejoining of DNA double-strand breaks (DSBs), slowing the fast component of rejoining significantly. However, these growth factors have no effect on the initial level of DSBs or on the percentage of residual unrejoined breaks at 120 min postirradiation. Both growth factors affect repair of lesions leading to dicentric, but not to acentric, chromosome aberrations significantly. In control cells (treated with phosphate-buffered saline, 90 min prior to irradiation), the half-time for disappearance of dicentrics was 4.1 h (3.4 to 5.1 h), and 47.1 +/- 3.7% of the residual damage remained at 24 h postirradiation. Insulin and IGF-1 increased the half-time for disappearance of dicentrics to 5.2 h (3.9 to 7.7 h) and 5.7 h (5.5 to 5.9 h), respectively, and increased residual damage to 56.1 +/- 5.9% and 60.8 +/- 6.0%, respectively. Overall, these data show that insulin and IGF-1 inhibit PLD repair in A549 cells by mechanisms which are independent of changes in cell cycle parameters. The data suggest that the growth factors act by inducing changes in chromatin conformation which promote misrepair of radiation-damaged DNA.

In vitro effects of growth hormone (GH) and insulin‐like growth factor I and II (IGF‐I and ‐II) on chromosome fragility and p53 protein expression in human lymphocytes

“…This finding is consistent with the results of Jayanth et al [26], who recently reported that IGF-I inhibits the repair of potentially lethal radiation damage of DNA in human lung carcinoma cells. IGF-I significantly increased the spontaneous frequency of b/c and raised, in a dose-dependent manner, the bleomycininduced frequency of b/c.…”

JC virus large T‐antigen and IGF‐I signaling system merge to affect DNA repair and genomic integrity

“…These include enhanced radioresistance, which was found proportional to the IGF-IR protein level in mouse embryo fibroblasts and breast tumor cells (Turner et al, 1997); enhanced DNA repair via the IGF-I activated p38 signaling pathway in response to UV-mediated DNA damage (Heron-Milhavet and LeRoith, 2002); and delayed UVB-induced apoptosis via IGF-I-mediated activation of Akt, resulting in enhanced repair of DNA cyclobutane thymidine dimers in keratinocytes (Decraene et al, 2002). In contrast, one report suggested a delay in DNA repair of potentially lethal radiation damage observed in the presence of IGF-I and insulin treatments of A549 cells (Jayanth et al, 1995). Although these few reports indicate that the IGF-IR signaling may contribute to the development of drug resistance and/or DNA repair, it remains unclear whether the receptor affects DNA repair directly, or whether its strong antiapoptotic properties (Sell et al, 1995;D'Ambrosio et al, 1997;Valentinis et al, 1998) simply increase the resistance to genotoxic agents.…”

IGF-IR in neuroprotection and brain tumors

“…These include enhanced radioresistance proportional to the IGF-IR protein level in both mouse embryo fibroblasts and breast tumor cells (234), enhanced DNA repair via the IGF-I activated p38 signaling pathway in response to UV-mediated DNA damage (235, 236), and delayed UVB-induced apoptosis via IGF-I-mediated activation of Akt, resulting in enhanced repair of DNA cyclobutane thymidine dimers in keratinocytes (237). In contrast, one report notes a delay in DNA repair of potentially lethal radiation damage observed following IGF-I and insulin treatments of A549 cells (238). …”