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J. Biol. Chem., Vol. 279, Issue 6, 3941-3948, February 6, 2004

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Role of Insulin Receptor Substrates and Protein Kinase C- in Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Pancreatic Cancer Cells^*

Matthias Neid, Kaustubh Datta, Susann Stephan, Ila Khanna, Soumitro Pal, Leslie Shaw, Morris White¶, and Debabrata Mukhopadhyay||**

From the Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, ^¶Research Division, Joslin Diabetes Center and Program in Biological Sciences, Harvard Medical School, and Division of Nephrology, Department of Medicine, Children's Hospital, Boston, Massachusetts 02115 and the ^||Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota 55905

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), the critical molecule in tumor angiogenesis, is regulated by different stimuli, such as hypoxia and oncogenes, and also by growth factors. Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor (IGF-IR) regulates VPF/VEGF expression. Insulin receptor substrate-1 and -2 (IRS-1 and IRS-2), two major downstream molecules of IGF-1R, are known to be important in the genesis of diabetes. In this study, we have defined a new role of IRS in angiogenesis. Both of the IRS proteins modulate VPF/VEGF expression in pancreatic cancer cells by different mechanistic pathways. The Sp1-dependent VPF/VEGF transcription is regulated mainly by IRS-2. Protein kinase C- (PKC-) plays a central role in VPF/VEGF expression and acts as a switching element. Furthermore, we have also demonstrated that the phosphatidylinositol 3-kinase pathway, but not the Ras pathway, is a downstream event of IRS proteins for VPF/VEGF expression in AsPC-1 cells. Interestingly, like renal cancer cells, in AsPC-1 cells PKC- leads to direct Sp1-dependent VPF/VEGF transcription; in addition, it also promotes a negative feedback loop to IRS-2 that decreases the association of IRS-2/IGF-1R and IRS-2/p85. Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1-dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC- to IRS-2. Our data also suggest that IRS proteins, which are known to play crucial roles in IGF-1R signaling, are also important mediators for tumor angiogenesis.

Received for publication, April 15, 2003 , and in revised form, October 10, 2003.

^* This work was supported in part by the American Cancer Society and National Institutes of Health Grants HL70567 and CA7838 (to D. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Mayo Clinic, Gugg 1401A, 200 First St., S. W., Rochester, MN 55905. Tel.: 507-538-3581; Fax: 507-284-1767; E-mail: mukhopadhyay.debabrata{at}mayo.edu.

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