EGFR Tyrosine Kinase Inhibitors Decrease VEGF Expression by Both Hypoxia-Inducible Factor (HIF)-1–Independent and HIF-1–Dependent Mechanisms

Abstract

Epidermal growth factor receptor (EGFR) inhibitors can decrease vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. In the current study, we investigate the molecular pathways by which this occurs using two drugs that have been used in the clinic, gefitinib (Iressa) and erlotinib (Tarceva). The decrease in VEGF expression by gefitinib in SQ20B squamous cell carcinoma cells was opposed by adenoviral expression of Akt in these cells. The hypoxia-inducible factor-1 (HIF-1) binding site located at approximately À1 kbp in the VEGF promoter was not required for down-regulation of promoter activity by gefitinib under normoxia. Furthermore, the drug decreased activity of a reporter containing the À88/ +54 region. In a gel shift assay, gefitinib led to decreased retardation of a labeled DNA oligonucleotide probe corresponding to the À88/À66 region of the VEGF promoter, which contains Sp1 binding sites. These effects of gefitinib on VEGF promoter activity and DNA binding were both reversed by Akt expression. Phosphorylation of Sp1 was decreased in the presence of gefitinib. Gefitinib also decreases VEGF expression by decreasing HIF-1A expression. This occurs due to decreased protein translation without any change in the level of HIF-1A mRNA. Together, these results suggest that gefitinib decreases VEGF expression both by decreasing Sp1 binding to the proximal core VEGF promoter and by down-regulating HIF-1A expression. Similar results were obtained with erlotinib in SQ20B and gefitinib in HSC3 squamous carcinoma cells. These results indicate that there are at least two separate mechanisms by which EGFR inhibitors decrease VEGF expression. (Cancer Res 2006; 66(6): 3197-204)

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

“…However, little was known about the mechanism of FSH stimulation on VEGF expression. Other studies showed HIF-1α and survivin may play a role in VEGF expression [7][8][9][10][13][14][15][16], and it had also been shown that FSH induces HIF-1α and survivin expression [37][38][39]. In this study, we showed that treatment with FSH also increased survivin and HIF-1α expression (Figure 2A and 2B).…”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…Lee et al 2000;Winkler et al 2004;Dings et al 2007;Fischer et al 2007;Eichhorn et al 2008;Batra et al 2009;Skuli et al 2009;McGee et al 2010. j Teicher et al 1995bJain et al 1998;Bernsen et al 1999;Cohen-Jonathan et al 2001;Delmas et al 2003;Ansiaux et al 2005Ansiaux et al , 2006Pore et al 2006b;Segers et al 2006;Cerniglia et al 2009;Qayum et al 2009;Cham et al 2010. k Ader et al 2003;Hamzah et al 2008;Kashiwagi et al 2008;Stockmann et al 2008;Maione et al 2009;Mazzone et al 2009;Skuli et al 2009;Tsukada et al 2009;Rolny et al 2011. l Yuan et al 1996Lee et al 2000;Wildiers et al 2003;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Kurozumi et al 2007;Taguchi et al 2008;Zhou et al 2008;Kamoun et al 2009;Ohta et al 2009;Gallo 2009. m Jain et al 1998;Izumi et al 2002;…”

Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy

“…In fact, overwhelming evidence indicates that HIF-a is indeed overexpressed in the majority of human cancers (17)(18)(19), where it is associated with patient mortality and poor response to treatment (20)(21)(22)(23)(24), findings that can be hardly reconciled with a negative role of HIF-1 in tumor growth. Importantly, the association of several oncogenic and receptor tyrosine kinase -dependent signaling pathways, frequently deregulated in human cancers, with HIF-1a activation also suggests that many of these pathways converge on or implicate HIF-1 in mediating cell survival and growth (25)(26)(27)(28). However, staining of HIF-1a in human cancers is variable, from few positive cells up to the majority of tumor tissue, and characterized by distinct patterns of expression, of which the implications and biological consequences are still poorly understood.…”