Insulin- and insulin-like growth-factor-I receptor tyrosine-kinase activities in human renal carcinoma
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M Kellerer1, H von Eye Corleta, A Mühlhöfer
1Institut für Diabetesforschung, Munich, Germany.
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.
Insights
Renal cell carcinoma exhibits increased insulin and IGF-I receptor levels and activity. This enhanced tyrosine-kinase activity in kidney cancer is not due to altered insulin receptor isoform expression.
Area of Science:
- Oncology
- Molecular Endocrinology
- Biochemistry
Background:
- Insulin and Insulin-like Growth Factor-I (IGF-I) receptors play crucial roles in cell growth and metabolism.
- Dysregulation of these receptors is implicated in various cancers, including renal carcinoma.
- Understanding receptor characteristics in renal cell carcinoma is vital for potential therapeutic strategies.
Purpose of the Study:
- To investigate the expression and functional characteristics of insulin and IGF-I receptors in human renal carcinoma.
- To compare receptor binding affinities, tyrosine-kinase activity, and isoform expression between tumor and normal kidney tissues.
- To elucidate the role of receptor alterations in the development or progression of renal cell carcinoma.
Main Methods:
- Analysis of ligand-binding properties and tyrosine-kinase activity of insulin and IGF-I receptors.
- Quantification of specific insulin and IGF-I binding sites in renal carcinoma and adjacent normal kidney tissue.
- Determination of insulin/IGF-I receptor hybrid content using tracer binding assays.
- Assessment of insulin receptor isoform (HIR-A and -B) mRNA levels via quantitative analysis.
Main Results:
- Renal cell carcinoma tissues showed 3- to 4-fold higher insulin binding and 2-fold higher IGF-I binding sites compared to normal kidney tissue.
- Receptor tyrosine-kinase activity, including autophosphorylation and substrate phosphorylation, was significantly elevated in carcinoma tissue.
- Similar levels of insulin/IGF-I receptor hybrids were observed in both normal and tumor tissues.
- The expression ratios of HIR-A and -B isoforms varied significantly in both normal and tumor tissues, not explaining the kinase activity differences.
Conclusions:
- Human renal carcinoma exhibits increased expression of insulin and IGF-I receptor proteins.
- Elevated tyrosine-kinase activity of these receptors in renal cell carcinoma is a key finding.
- The enhanced receptor activity is not attributable to altered expression patterns of insulin receptor isoforms HIR-A and -B.