Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells.

Abstract

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-zeta (PKC-zeta) 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-zeta 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-zeta 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.

• Authors: Matthias Neid, Kaustubh Datta, Susann Stephan, Ila Khanna, Soumitro Pal, Leslie Shaw, Morris White, Debabrata Mukhopadhyay
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 6 Pg. 3941-8 (Feb 06 2004) ISSN: 0021-9258 [Print] United States
• PMID: 14604996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Neoplasm
• IRS1 protein, human
• IRS2 protein, human
• Insulin Receptor Substrate Proteins
• Intracellular Signaling Peptides and Proteins
• Phosphoproteins
• Sp1 Transcription Factor
• Vascular Endothelial Growth Factor A
• protein kinase C zeta
• Protein Kinase C

Topics

• Adenocarcinoma (blood supply, genetics, metabolism)
• Base Sequence
• Cell Line, Tumor
• DNA, Neoplasm (genetics)
• Feedback
• Gene Expression Regulation, Neoplastic
• Humans
• Insulin Receptor Substrate Proteins
• Intracellular Signaling Peptides and Proteins
• Neovascularization, Pathologic
• Pancreatic Neoplasms (blood supply, genetics, metabolism)
• Phosphoproteins (metabolism)
• Protein Kinase C (metabolism)
• Signal Transduction
• Sp1 Transcription Factor (metabolism)
• Vascular Endothelial Growth Factor A (genetics)