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Enhanced expression of the insulin receptor substrate-2 docking protein in human pancreatic cancer
M Kornmann1, H Maruyama, U Bergmann
1Department of Medicine, University of California, Irvine 92697, USA.
Abstract:
Insulin receptor substrate-2 (IRS-2) is a multisite docking protein implicated in mitogenic signaling after activation of the insulin and insulin-like growth factor (IGF)-I receptors. In the present study, we characterized IRS-2 expression and function in human pancreatic cancer. IRS-2 mRNA and protein were expressed in ASPC-1 and COLO-357 human pancreatic cancer cell lines. Insulin, IGF-I, and IGF-II enhanced the growth of both cell lines, stimulated tyrosine phosphorylation of IRS-2, and increased IRS-2-associated phosphatidylinositol (PI) 3-kinase activity. The mitogenic effects of insulin, IGF-I, and IGF-II were markedly attenuated by the PI 3-kinase inhibitor LY 294002. Northern blot analysis of total RNA extracted from normal and cancerous tissues revealed that IRS-2 mRNA levels were increased in the cancer tissues (P = 0.032). In the normal pancreas, IRS-2 immunoreactivity was present at low levels in some ductal and acinar cells and at moderate levels in a heterogeneous pattern in all of the endocrine islets. In the pancreatic cancers, IRS-2 was abundant in the ductal-like cancer cells. These findings indicate that IRS-2 is overexpressed in human pancreatic cancer and suggest that it may contribute to enhanced mitogenic signaling via the PI 3-kinase pathway, thereby leading to excessive growth stimulation in this malignancy.
Insights
Insulin receptor substrate-2 (IRS-2) is overexpressed in human pancreatic cancer. This protein may drive cancer growth by enhancing signaling through the phosphatidylinositol 3-kinase (PI3K) pathway.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Insulin receptor substrate-2 (IRS-2) is a key docking protein in mitogenic signaling pathways.
- IRS-2 mediates signals from insulin and insulin-like growth factor (IGF) receptors.
- Dysregulation of signaling pathways is common in cancer development.
Purpose of the Study:
- To investigate the expression and functional role of IRS-2 in human pancreatic cancer.
- To determine if IRS-2 contributes to the growth of pancreatic cancer cells.
Main Methods:
- Analysis of IRS-2 mRNA and protein expression in human pancreatic cancer cell lines (ASPC-1, COLO-357) and tissues.
- Stimulation of cell lines with insulin, IGF-I, and IGF-II.
- Assessment of IRS-2 tyrosine phosphorylation and associated phosphatidylinositol (PI) 3-kinase activity.
- Inhibition of PI 3-kinase activity using LY 294002.
- Northern blot analysis for IRS-2 mRNA levels in normal and cancerous pancreatic tissues.
- Immunohistochemical analysis of IRS-2 expression in normal and cancerous pancreatic tissues.
Main Results:
- IRS-2 mRNA and protein were detected in human pancreatic cancer cell lines.
- Insulin, IGF-I, and IGF-II stimulated pancreatic cancer cell growth, IRS-2 phosphorylation, and PI 3-kinase activity.
- The PI 3-kinase inhibitor LY 294002 significantly reduced the mitogenic effects of insulin, IGF-I, and IGF-II.
- IRS-2 mRNA levels were significantly higher in cancerous pancreatic tissues compared to normal tissues (P = 0.032).
- IRS-2 was expressed at low levels in normal pancreatic cells but abundantly in ductal-like cancer cells.
Conclusions:
- IRS-2 is overexpressed in human pancreatic cancer.
- IRS-2 likely contributes to enhanced mitogenic signaling in pancreatic cancer via the PI 3-kinase pathway.
- Targeting IRS-2 or the PI 3-kinase pathway may represent a therapeutic strategy for pancreatic cancer.