Insulin‐and insulin‐like growth‐factor‐I receptor tyrosine‐kinase activities in human renal carcinoma

Abstract

We studied expression and functional characteristics of the insulin- and insulin-like-growth-factor-I (IGF-I) receptors in human renal carcinoma. Ligand-binding properties and tyrosine-kinase activity of both receptors, as well as the expression of the 2 isoforms of the human insulin receptor (HIR-A and -B) were analyzed in renal carcinoma and normal adjacent kidney tissue of 8 adult patients. Partially purified insulin- and IGF-I receptors from normal and renal cell carcinoma tissue possessed identical affinities for their ligands. Renal cell carcinoma, however, contained 3- to 4-fold more specific insulin-binding sites and 2-fold more IGF-I binding sites than adjacent normal kidney tissue. In addition, we determined the relative content of insulin/IGF-I receptor hybrids in both tissues. Renal cell carcinoma and adjacent normal tissue revealed similar amounts of insulin/IGF-I receptor hybrids, i.e., 44 +/- 8.2% of tracer IGF-I binding in normal tissue and 46 +/- 12.0% in renal cell carcinoma. When equal amounts of insulin- and IGF-I receptor protein were studied, we found significantly increased receptor autophosphorylation and elevated substrate phosphorylation in carcinoma tissue. To assess whether the differences in insulin-receptor tyrosine-kinase activity were caused by an altered pattern of insulin receptor isoform expression, we determined mRNA levels for HIR-A and -B. The 2 insulin receptor isoforms were, however, expressed in highly variable ratios in both normal and tumor tissue. Our experiments show that renal carcinoma expresses an elevated amount of insulin- and IGF-I receptor protein with increased specific autophosphorylation and tyrosine-kinase activity each. The increase of insulin-receptor tyrosine-kinase activity in renal carcinoma cannot be explained by an altered expression pattern of insulin receptor isoforms.

Lifetime physical activity and the risk of renal cell cancer

“…21,23 Another proposed mechanism is the reduction of lipid peroxidation, which, in turn, has been shown to react with renal cell DNA to form adducts, which may lead to mutations. 24 Other mechanisms relate to the link between physical inactivity, specific dietary patterns (i.e., a diet rich in refined carbohydrates, fat, dairy foods and high energy intake), propensity to overweight and obesity, which may lead to higher risk.…”

Obesity and renal cell cancer – a quantitative review

“…Increasing BMI is accompanied by elevated levels of fasting serum and free insulinlike growth factor-I (IGF-I) among both men and women (Frystyk et al, 1995). Insulin and IGF-I could both contribute to the growth and proliferation of renal cell cancer (Kellerer et al, 1995). Epidemiological studies indicate that patients with diabetes, which is associated with higher plasma insulin levels, have an increased risk of renal cell cancer (Schlehofer et al, 1996;Lindblad et al, 1999).…”

Epidemiologic characteristics and risk factors for renal cell cancer

“…Obesity may promote changes in circulating levels of estrogen and other steroid hormones, or elevated levels of insulin-like growth factor-I (IGF-I), which could in turn contribute to the development of renal cell cancer. [87][88][89][90] Lipid peroxidation, which is increased among obese subjects, has been hypothesized to be partly responsible for the association of obesity with renal cell cancer through the formation of DNA adducts. 91 Other conjectured mechanisms include elevated cholesterol level and down-regulation of low-density lipoprotein receptor, lower levels of vitamin D, and increases in adipose tissue-derived hormones and cytokines, such as leptin and adiponectin.…”