TY - JOUR
T1 - Role of Insulin Receptor Substrates and Protein Kinase C-ζ in Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Pancreatic Cancer Cells
AU - Neid, Matthias
AU - Datta, Kaustubh
AU - Stephan, Susann
AU - Khanna, Ila
AU - Pal, Soumitro
AU - Shaw, Leslie
AU - White, Morris
AU - Mukhopadhyay, Debabrata
PY - 2004/2/6
Y1 - 2004/2/6
N2 - 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-ζ (PKC-ζ) 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-ζ 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-ζ 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.
AB - 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-ζ (PKC-ζ) 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-ζ 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-ζ 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.
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U2 - 10.1074/jbc.M303975200
DO - 10.1074/jbc.M303975200
M3 - Article
C2 - 14604996
AN - SCOPUS:1042301429
SN - 0021-9258
VL - 279
SP - 3941
EP - 3948
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -