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Opposing Roles for the Insulin-Like Growth Factor (IGF)-II and Mannose 6-Phosphate (Man-6-P) Binding Activities of the IGF-II/Man-6-P Receptor in the Growth of Prostate Cancer Cells

Department of Biochemistry and Molecular Biology (B.S.S., M.-F.L., J.C.B., R.G.M.), University of Nebraska Medical Center, Omaha, Nebraska 68198-4525; and Division of Life Sciences (J.H.Y.P.), Hallym University, Chunchon, Korea 200-702

Address all correspondence and requests for reprints to: Richard G. MacDonald, Ph.D., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, Nebraska 68198-4525. E-mail: rgmacdon{at}unmc.edu.

The IGF-II/mannose 6-phosphate (Man-6-P) receptor (IGF2R) binds IGF-II and Man-6-P-bearing ligands at distinct binding sites. Analysis of IGF2R expression and function suggested that decreased IGF2R expression could partly account for the increased growth of lymph node carcinoma of the prostate (LNCaP) human prostate cancer cells observed with increasing passage in culture. However, LNCaP cells that expressed a Myc-tagged IGF2R (IGF2RMyc) proliferated more rapidly than control cells transfected with the empty vector. LNCaP cells expressing a mutant IGF2R incompetent to bind IGF-II (IGF2RMyc I/T) proliferated more rapidly than both vector-transfected cells and cells expressing the IGF2RMyc. In contrast, forced expression of IGF2RMyc in PC-3 human prostate cancer cells resulted in decreased proliferation, compared with control cells. As in LNCaP cells, PC-3 cells expressing IGF2RMyc I/T proliferated more rapidly than vector-transfected cells. The subcellular distribution and ability to internalize cell-surface IGF-II of IGF2RMyc were indistinguishable from endogenous IGF2R in PC-3 cells. These data suggest that the IGF-II- and Man-6-P-binding functions of the IGF2R have opposing activities, with respect to growth of prostate cancer cells. The magnitude of each activity in a given cell type seems to determine whether the net effect of the IGF2R on cell growth is inhibitory or stimulatory.

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