Role of Insulin Receptor Substrates and Protein Kinase C-ζ 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, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish (US)
Pages (from-to)3941-3948
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
StatePublished - Feb 6 2004

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Insulin Receptor Substrate Proteins
Pancreatic Neoplasms
Protein Kinase C
Vascular Endothelial Growth Factor A
Cells
Transcription
Tumors
Proteins
Phosphatidylinositol 3-Kinase
Somatomedin Receptors
Feedback
Molecules
Insulin-Like Growth Factor II

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Role of Insulin Receptor Substrates and Protein Kinase C-ζ in Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Pancreatic Cancer Cells. / Neid, Matthias; Datta, Kaustubh; Stephan, Susann; Khanna, Ila; Pal, Soumitro; Shaw, Leslie; White, Morris; Mukhopadhyay, Debabrata.

In: Journal of Biological Chemistry, Vol. 279, No. 6, 06.02.2004, p. 3941-3948.

Research output: Contribution to journalArticle

Neid, Matthias ; Datta, Kaustubh ; Stephan, Susann ; Khanna, Ila ; Pal, Soumitro ; Shaw, Leslie ; White, Morris ; Mukhopadhyay, Debabrata. / Role of Insulin Receptor Substrates and Protein Kinase C-ζ in Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Pancreatic Cancer Cells. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 6. pp. 3941-3948.
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