Nuclear insulin-like growth factor-1 receptor (IGF1R) displays proliferative and regulatory activities in non-malignant cells

Abstract

The insulin-like growth factor-1 receptor (IGF1R) mediates the biological actions of IGF1 and IGF2. The IGF1R is involved in both physiological and pathological activities and is usually overexpressed in most types of cancer. In addition to its classical mechanism of action, recent evidence has shown a nuclear presence of IGF1R, associated with novel genomic/transcriptional types of activities. The present study was aimed at evaluating the hypothesis that nuclear IGF1R localization is not restricted to cancer cells and might constitute a novel physiologically relevant regulatory mechanism. Our data shows that nuclear translocation takes place in a wide array of cells, including normal diploid fibroblasts. In addition, we provide evidence for a synergistic effect of a nuclear translocation blocker along with selective IGF1R inhibitors in terms of decreasing cell proliferation. Given the important role of the IGF1R in mitogenesis, the present results may be of translational relevance in cancer research. In conclusion, results are consistent with the concept that nuclear IGF1R fulfills important physiological and pathological roles.

Characterization of an activating R1353H insulin-like growth factor 1 receptor variant in a male with extreme tall height

“…These functions are believed to be through the nuclear portion of IGF-1R (nIGF-1R). Even though nIGF-1R was discovered in cancer cell lines, recent evidence has shown the existence of nIGF1R in non-malignant cells, including normal diploid fibroblasts (31). Effects on such mechanisms could explain the observed gene expression differences.…”

Glioma Cells With Genetically Engineered IGF-I Receptor Downregulation Can Persist in the Brain in a Dormant State

“…This dual, high affinity binding may also limit the efficacy of therapeutic strategies designed to target individual ligands (32) and underlines the importance of targeting the receptor (9,32) or both ligands. Targeting IGF-IR expression using strategies such as gene therapy also has the added advantage of reducing the levels of receptor available to translocate to the nucleus, where it was shown to play a regulatory role, independent of its membrane-bound functions (33).…”

“Immunolocalization and effect of low concentrations of Insulin like growth factor‐1 (IGF‐1) in the canine ovary”

“…The presence of nuclear IGF‐1R was initially described in human tumour cells and no malignant tissues characterized by a high proliferation rate (Aleksic et al., 2010). However, a recent study has shown that the nuclear IGF‐1R is not restricted to tumour cells but it is also present in normal cells (Solomon‐Zemler et al., 2017). The intracellular localization of IGF‐1 and its receptor may constitute a potential regulatory mechanism of the ovarian function in the bitch.…”

“…In addition, both pathways are involved in oocyte maturation through the activation of the maturation‐promoting factor (MPF) that facilitates the entry into M‐phase of meiosis I and II (Kishimoto, 2003). It has been demonstrated that insulin like growth factor promotes maturation and expansion of cumulus cells (Mazerbourg et al., 2003), and can also inhibit apoptosis in ovarian cells (Solomon‐Zemler, Sarfstein, & Werner, 2017; Wasielak & Bogacki, 2007).…”