Insulin-like growth factor-1 signaling in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells.

MicroRNA‑877 inhibits cell proliferation and invasion in non‑small cell lung cancer by directly targeting IGF‑1R

“…IGF-1R is a transmembrane tyrosine kinase receptor of the insulin receptor family and contains two extracellular α subunits and two transmembrane β subunits (45). Numerous studies have reported that IGF-1R is frequently overexpressed in a variety of human cancer types, including gastric cancer (46), breast cancer (47), glioblastoma (48), renal cell carcinoma (49) and osteosarcoma (50). In NSCLC, IGF-1R expression has been revealed to be upregulated, and significantly associated with tumor size, tumor grade and response to chemotherapy (25)(26)(27)(28)(29)(30).…”

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

“…p53 is one of the most frequently mutated tumor suppressors and IGF1R overexpression inhibits wild-type p53 (WT-p53) via phosphorylated (p) AKT (80). This enhances the ubiquitination-promoting function of murine double minute 2, which decreases p53 protein production (79). Reciprocally, WT-p53 renders tumor cells more chemosensitive by inhibiting Sp1-induced transactivation of the IGF1R promoter and increasing the expression of pro-apoptotic protein p21 (81).…”

“…Previous studies have indicated that cancer chemotherapy is associated with inducing p53-dependent apoptosis responses (79). p53 is one of the most frequently mutated tumor suppressors and IGF1R overexpression inhibits wild-type p53 (WT-p53) via phosphorylated (p) AKT (80).…”

“…Anti-apoptosis is common to numerous tumors and chemotherapy-resistant cells evolve diverse strategies to limit or avoid apoptosis (3). The most common strategy is to eliminate the tumor suppressor function of p53 (79). Resistant cells also downregulate pro-apoptotic factors or increase the expression of anti-apoptotic factors to avoid apoptosis (80).…”

Prognostic Importance of Vitamins A, E and Retinol-binding Protein 4 in Renal Cell Carcinoma Patients

“…This protein is produced by adipose cells and affects the negative feedback regulation of glucose transporter type 4, which leads to a decreased insulin sensitivity in fat and other tissues (5). Insulin-like growth factor-1 (IGF-1), which is also a prognostic RCC factor at the time of diagnosis, may be a potential mediator between obesity and RCC development (6). However, the relationship between RBP4 and RCC has not been sufficiently tested.…”