Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells.
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.
Neid
Matthias
M
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Datta
Kaustubh
K
Stephan
Susann
S
Khanna
Ila
I
Pal
Soumitro
S
Shaw
Leslie
L
White
Morris
M
Mukhopadhyay
Debabrata
D
D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D005246:Feedback; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D000099221:Protein Kinase C zeta
D004273:DNA, Neoplasm; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000099221:Protein Kinase C zeta; C526292:IRS1 protein, human; C526297:IRS2 protein, human