Nuclear IGF1R interacts with NuMA and regulates 53BP1‑dependent DNA double‑strand break repair in colorectal cancer.

Abstract

Nuclear insulin-like growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitation-coupled mass spectrometry was performed in an IGF1R-overexpressing SW480-OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA double-strand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53-binding protein 1 (53BP1)-NuMA colocalization between IGF1R-positive (R+) and IGF1R-negative (R−) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R− cells during IR-induced DNA damage. By contrast, the level of NuMA-53BP1 was markedly lower in R+ cells compared with R− cells. The present data suggested a regulatory role of nIGF1R in 53BP1-dependent DSB repair through its interaction with NuMA. Bright-field PLA analysis on a paraffin-embedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA-53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1-dependent DDR by regulating the NuMA-53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.