Journal Article

The roles of IGF-I and IGFBP-3 in the regulation of proximal tubule, and renal cell carcinoma cell proliferation

Cheung, Catherine W., Vesey, David A., Johnson, David W., Nicol, David L.

2004

Overview

The roles of IGF-I and IGFBP-3 in the regulation of proximal tubule, and renal cell carcinoma cell proliferation. Insulin-like growth factor I (IGF-I), a potent proximal tubule cell (PTC) mitogen, has been implicated in the progression of many human cancers. Our previous work on human renal tissues has suggested that IGF-I and several of its binding proteins (IGFBP-3 and -6) are up-regulated in clear cell renal cell carcinoma (RCC). To further elucidate the role of IGF-I and IGFBPs in RCC growth, immunohistochemistry, thymidine incorporation, and Western analysis were performed in primary cultures of normal PTC (priPTC) and clear-cell RCC (priRCC), as well as in SN12K1 cells (a cell line derived from metastatic RCC). By immunohistochemistry, IGFBP-3 and IGF-I were prominently expressed in SN12K1 cells, and weakly expressed in priPTC and priRCC. Incubation with 100ng/mL IGF-I significantly augmented DNA synthesis by priPTC (mean ± SD 120.7%± 19.7% of controls, P < 0.05), priRCC (238.7%± 279.9% of controls, P < 0.01), and SN12K1(120.0%± 22.9% of controls, P < 0.05). Neutralizing antibodies to IGF-I and IGF-I receptor significantly suppressed SN12K1 growth (81.9%± 13.5% of control, P < 0.01 and 87.4%± 16.2% of control, P < 0.05, respectively). Removal of endogenous IGFBP-3 by an anti-IGFBP-3 increased SN12K1 DNA synthesis (243.9%± 35.3% of control, P < 0.001), which was partially abrogated by coincubation with exogenous IGFBP-3 (135.97%± 5.9% of controls, P < 0.001). Using Western analysis, IGFBP-3 expression was enhanced in IGF-I–stimulated SN12K1 cells exposed to exogenous IGF-I. Coincubation with anti-IGFBP-3 further enhanced IGF-I–induced DNA synthesis. RCC cells express IGF-I and IGFBP-3, and are responsive to exogenous IGF-I stimulation. Moreover, in SN12K1 cells (derived from metastatic RCC), autocrine IGF-I and IGFBP-3 actions, respectively, stimulated and inhibited growth. These results suggest that IGF-I and IGFBP-3 may be potential candidates for therapeutic manipulation in patients with advanced RCC.

• Publisher: Elsevier Inc,Nature Publishing,Elsevier Limited
• Subject: Antibodies - pharmacology / Biological and medical sciences / Carcinoma, Renal Cell - metabolism / Carcinoma, Renal Cell - pathology / Carcinoma, Renal Cell - secondary / Cell Division - drug effects / Cell Division - physiology / Cells, Cultured / DNA - biosynthesis / DNA synthesis / Humans / immunohistochemistry / insulin-like growth factor binding protein 3 / Insulin-Like Growth Factor Binding Protein 3 - metabolism / Insulin-Like Growth Factor Binding Protein 3 - pharmacology / insulin-like growth factor I / Insulin-Like Growth Factor I - antagonists & inhibitors / Insulin-Like Growth Factor I - immunology / Insulin-Like Growth Factor I - metabolism / Insulin-Like Growth Factor I - pharmacology / Kidney Neoplasms - metabolism / Kidney Neoplasms - pathology / Kidney Neoplasms - secondary / Kidney Tubules, Proximal - cytology / Kidney Tubules, Proximal - metabolism / Kidneys / Medical sciences / Nephrology. Urinary tract diseases / renal cell carcinoma / Tumors of the urinary system / Western blotting