Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer.
Activation of the insulin-like growth factor-I receptor (IGF-IR) was recently shown to modulate angiogenesis by up-regulating the expression of vascular endothelial growth factor (VEGF). We hypothesized that inhibiting IGF-IR function would inhibit angiogenesis and growth of pancreatic cancer in vivo and sought to identify major signaling pathways regulated by IGF-IR in pancreatic cancer cells. Human pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative form of IGF-IR (IGF-IR DN) or an empty vector (pcDNA). In vitro, IGF-IR DN cells exhibited a decrease in both constitutive and inducible phosphorylation of IGF-IR and Erk1/2. Constitutive expression of nuclear hypoxia-inducible factor-1alpha and secreted VEGF (P < 0.01) protein levels also were significantly lower in IGF-IR DN cells than in pcDNA cells. In vivo, IGF-IR inhibition led to decreases in pancreatic tumor volume and weight, vessel density, and tumor cell proliferation (P < 0.01 for all) and increases in tumor cell apoptosis (P < 0.02). Our results suggest that autocrine activation of the IGF-IR system significantly affects VEGF expression and angiogenesis in human pancreatic cancer. Thus, IGF-IR may be a valid target in the treatment of pancreatic cancer.
Stoeltzing
Oliver
O
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Liu
Wenbiao
W
Reinmuth
Niels
N
Fan
Fan
F
Parikh
Alexander A
AA
Bucana
Corazon D
CD
Evans
Douglas B
DB
Semenza
Gregg L
GL
Ellis
Lee M
LM
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017209:Apoptosis; D019898:Autocrine Communication; D002455:Cell Division; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008024:Ligands; D008222:Lymphokines / Q000378:metabolism*; D008565:Membrane Proteins; D006899:Mixed Function Oxygenases; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011451:Prostaglandin-Endoperoxide Synthases; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008024:Ligands; D008222:Lymphokines; D008565:Membrane Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017526:Receptor, IGF Type 1