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.

Keywords: IGF-1 receptor (IGF1R); Insulin-like growth factor-1 (IGF-1); Renal cell carcinoma (RCC; ccRCC).

Fig. 1

Schematic representation of downstream signaling of IGF1R. AKT, protein kinase B; AMPK, AMP-activated protein kinase; Bcl-2, B-cell lymphoma 2; BAD, B-cell CLL/lymphoma 2 antagonist of cell death; ERK 1/2, extracellular-signal-regulated kinase 1/2, IGF1R, insulin-like growth factor 1 receptor; IR, insulin receptor; IRS1-4, insulin-like receptor substrate 1–4; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; PI3K/AKT, phosphatidylinositol 3-kinase/AKT; PDK1, 3-phosphoinositide-dependent protein kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; GLUT4, Glucose transporter type 4; HIF-1α, Hypoxia-inducible factor 1-alpha, VEGF, Vascular endothelial growth factor

Fig. 2

Schematic representation of promoter region of IGF1R and its main transcription factors. Sp1, Specificity protein 1; HMGA1, High mobility group A1; KLF6, Krüppel-like factor 6; E2F1, E2F family of transcription factors; POL, RNA polymerase II; TBP, TATA-binding protein; GC, GC boxes; INR, initiator element

Fig. 3

Regulation of promoter activity of IGF1R gene by tumor suppressor genes. POL, RNA polymerase II; TBP, TATA-binding protein; GC, GC boxes; INR, initiator element