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 Rcells during IR-induced DNA damage. By contrast, the level of NuMA-53BP1 was markedly lower in R + cells compared with Rcells. 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.

Insights on the Biomarker Potential of Exosomal Non-Coding RNAs in Colorectal Cancer: An In Silico Characterization of Related Exosomal lncRNA/circRNA–miRNA–Target Axis

“…The literature review revealed that the vast majority of the identified genes had previously been linked to colorectal cancer pathogenesis. Of these genes, the ones that seem to have an important role in CRC are EZH2, PTEN, EGFR, IGF1, HGF, SMAD4 and PTGS2 [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ].…”

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

“…Clinical and experimental evidence suggests strong potential for IGF-1-R antagonists to overcome resistance to anti-cancer chemotherapy drugs ( 40 , 47 – 49 ). For instance, manuka honey restored the ability of metastatic colorectal cancer first-line drug 5-fluorouracil to abrogate resistance to apoptosis of cancer stem-like cells derived from the HCT-116 colon adenocarcinoma cell line by a pleiotropic mechanism involving the downregulation of IGF-1, IGF-2, IGF-1R, as well as other inhibitors of apoptosis, such as: inhibitors of apoptosis protein (IAP) family members survivin, livin, and XIAP; and heat shock proteins HSP-27, HSP-60, and HSP-70 ( 47 ).…”

“…5 Therapeutic potential of IGF-1-R targeting in cancer 5.1 IGF-1R silencing can abrogate cancer drug resistance in vitro It appears from the data presented above that IGF-1-R signaling targeting could be an excellent therapeutic strategy in cancer, particularly in chemotherapy resistant cases (Figure 4). Other examples include the recently reported ability of nuclear IGF-1R to drive chemotherapy resistance in various types of cancer, and notably, through interactions with nuclear mitotic apparatus (NuMA) protein and regulating p53−binding protein 1 (53BP1) −dependent DNA double−strand break repair in colorectal cancer (40). Resistance to osimertinib, a thirdgeneration tyrosine kinase inhibitor targeting EGF receptor used as first-line therapy for patients with non-small cell lung cancer (NSCLC) harboring mutant EGFR, is mediated by IGF-1R signaling activated by IGF-2 in NSCLC cell lines (41).…”

53BP1: Keeping It under Control, Even at a Distance from DNA Damage

“…Moreover, it has been proposed that the nuclear insulin-like growth factor 1 receptor (nIGF1R) facilitates a 53BP1-dependent DDR by regulating the NuMA–53BP1 interaction. Indeed, this interaction was reduced in IGF1R-negative mouse embryonic fibroblasts [ 154 ].…”