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Research Articles: Targets

Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1 activity and vascular endothelial growth factor expression in small cell lung cancer cells

Department of Medicine, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia

Requests for reprints: Geoffrey W. Krystal, Richmond Veterans Affairs Medical Center (111K), 1201 Broad Rock Boulevard, Richmond, VA 23249. Phone: 804-675-5446; Fax: 804-675-5447. E-mail: gkrystal{at}hsc.vcu.edu

Vascular endothelial growth factor (VEGF) is one of the most important mediators of tumor angiogenesis. In addition to hypoxia, peptide growth factors are known to regulate VEGF expression but the effect of stem cell factor (SCF), the ligand for c-Kit, on VEGF expression has not been characterized. We therefore studied the effect of SCF-mediated c-Kit activation on VEGF expression by the H526 small cell lung cancer (SCLC) cell line. SCF treatment doubled VEGF mRNA expression and VEGF secretion in the absence of other exogenous growth factors, an effect efficiently blocked by imatinib. The increase in VEGF mRNA occurred within the first 2 hours of treatment and was not caused by alterations in mRNA stability. The phosphatidylinositol 3-kinase inhibitor LY294002 blocked the increase in VEGF mRNA, implicating c-Kit-mediated activation of phosphatidylinositol 3-kinase in the phenomenon. VEGF promoter-reporter transfections indicated that a SCF-mediated increase in VEGF promoter activity paralleled the increase in VEGF mRNA, documenting that SCF mediated its effects through enhanced VEGF transcription. Mutation of the core hypoxia-inducible factor (HIF)-1 binding element in the VEGF promoter significantly blunted SCF-responsiveness. SCF increased nuclear levels of the HIF-1 transcription factor, which correlated well with increased HIF-1 binding to a consensus hypoxia-responsive element. SCF-mediated effects on HIF-1 expression were additive with those produced by CoCl₂, a hypoxia-mimetic agent. These data indicate that activation of c-Kit by SCF leads to a predominantly HIF-1-mediated enhancement of VEGF expression and that inhibition of c-Kit signaling with imatinib could result in inhibition of tumor angiogenesis. [Mol Cancer Ther 2006;5(6):1415–22]

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Received 12/ 1/05; revised 3/ 2/06; accepted 4/13/06.