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 cancer, 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.
Footnotes
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↵1 Supported by NIH Grant CA-40162 (to Mu. K.). Ma. K. was the recipient of postdoctoral fellowship awards Ko 1716/1-1 and 1-2 from the Deutsche Forschungsgemeinschaft. U. B. was the recipient of postdoctoral fellowship award Be 1762/1-1 from the Deutsche Forschungsgemeinschaft.
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↵2 To whom requests for reprints should be addressed, at the Division of Endocrinology, Diabetes and Metabolism, Medical Sciences I, C240, University of California, Irvine, CA 92697. Phone: (714) 824-6887; Fax: (714) 824-1035; E-mail: mkorc@uci.edu.
- Received July 10, 1998.
- Accepted August 17, 1998.
- ©1998 American Association for Cancer Research.
Volume 58, Issue 19
