IGF-IR in neuroprotection and brain tumors

Abstract

The IGF-IR is a multifunctional tyrosine kinase receptor involved in several biological processes including cell proliferation, differentiation, DNA repair, and cell survival. In the brain IGF-I plays a critical role during embryonic and early postnatal development. In the mature brain, IGF-I binding sites have been found in different regions of the brain, and multiple reports confirmed a strong neuroprotective action of the IGF-IR against different pro-apoptotic insults. When the IGF-IR signaling system is insufficiently deployed, either by low level of expression in elderly individuals, or by the inhibition associated with inflammatory cytokines, neuronal function and survival could be compromised. The examples of such CNS pathologies include HIV associated dementia, diabetic neuropathies, and Alzheimer’s disease. On the other hand, elevated expression activity of the IGF-IR may support uncontrolled cell proliferation and protection from apoptosis. Probably the best example of the IGF-IR involvement in brain tumors is medulloblastomas in which functional cooperation between viral oncoprotein, JC virus large T-antigen, and IGF-IR has been recently established. Therefore, better understanding of the beneficial and potentially harmful aspects of the IGF-IR can be critical for the development of new clinical regimens against neurodegenerative disorders and brain tumors.

Fetal Growth, Preterm Birth, Neonatal Stress and Risk for CNS Tumors in Children: A Nordic Population- and Register-Based Case-Control Study

“…Furthermore, overexpression of components of the IGF pathway is observed in medulloblastoma, ependymoma, glioblastoma, and astrocytoma. Several reports have shown that the IGF-I receptor signaling pathway is highly active in medulloblastoma cell lines, animal models, and human tumor tissues (36). Finally, an effect of accelerated growth on carcinogenesis is supported by the increased risk for cancer observed in overgrowth syndromes, such as Beckwith-Wiedemann (37), Soto (38), and acromegaly (39).…”

“…A third explanation might be that the intrauterine presence of a CNS tumor could influence the overall growth rate of the fetus through endogenous hormonal mechanisms (36).…”

Insulin‐like growth factor‐I–forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor‐α‐mediated neuronal damage: Implications for human immunodeficiency virus encephalitis

“…This is mainly because of its multiple antiapoptotic signals (Baserga et al, 1997a; Peruzzi et al, 1999), the role of IGF-IR in protecting fetal brain tissue during development (Gualco et al, 2009a,b), and the supportive role of IGF-I in maintaining growth and survival of oli-godenrocyte progenitors (Arsenijevic et al, 2001; Hsieh et al, 2004). In addition to the antiapoptotic action of IGF-IR, IGF-I treatment can also counteract ROS accumulation in HG-treated mesanglial cells (Kang et al, 2003b; Yang et al, 2005), and HG-induced accumulation of intracellular ROS was partially inhibited by IGFI in PC12 neuron-like cells and in rat cortical neurons (this paper; Figs.…”

Estrogen Receptor-β Up-Regulates IGF1R Expression and Activity to Inhibit Apoptosis and Increase Growth of Medulloblastoma

“…Normal IGF-signaling is critical during cerebellar development and treatment with IGF-1 can protect GCP from pathological cell death (18 -20). The importance of IGFsignaling in tumorigenesis and progression of Med and other CNS malignancies is also well-established (21)(22)(23). In transgenic models of Med, disruption of the IGF and sonic hedgehog signaling pathways act synergistically to increase Med incidence (24).…”

“…In transgenic models of Med, disruption of the IGF and sonic hedgehog signaling pathways act synergistically to increase Med incidence (24). In human Med, increased expression of IGF1R and increased IGF-signaling are associated with increased tumor growth and decreased apoptosis (21,25). Inhibition of IGF1R has also been shown to decrease Med growth and to increase sensitivity of Med cells to cytotoxic chemotherapeutics (26,27).…”