Mutant IκBα Suppresses Hypoxia-Induced VEGF Expression Through Downregulation of HIF-1α and COX-2 in Human Glioma Cells

Abstract

Our previous study demonstrated that mutant IkappaBalpha (IkappaBalphaM) could inhibit glioma angiogenesis and tumorigenesis through the downregulation of vascular endothelial growth factor (VEGF) and IL-8. However, the pathways involved in VEGF expression are not well understood. Growing evidence indicates that hypoxia-inducible factor-1alpha (HIF-1alpha) and cyclooxygenases-2 (COX-2) play important roles in this progression. In this study, we first examined the expressions of hypoxia-induced genes in human glioma cells transfected with IkappaBalphaM (IN500deltaM) or control plasmid (IN500delta) in vitro. We found that hypoxic stress induced the expressions of HIF-1alpha, COX-2, and VEGF, and that IkappaBalphaM completely suppressed these expressions in vitro. Next, we injected these glioma cells into nude mice. After 3 weeks, the mice were moved to a hypoxic chamber (10% oxygen) for 3, 12, 24, 48, 96, or 144 h. The expressions of HIF-1alpha, COX-2, and VEGF in vivo were then analyzed by Northern blot and immunohistochemistry. IkappaBalphaM suppressed the expression of hypoxia-induced HIF-1alpha gene in vivo, but hypoxic stress induced the expression of COX-2 after 72 h. VEGF induction followed after 96 h of hypoxia in IN500deltaM cells. These findings suggest that VEGF expression appears to be regulated through dual interdependent mechanisms involving HIF-1 and COX-2 genes, and IkappaBalphaM could inhibit VEGF expression through these two pathways. Thus, IkappaBalphaM is identified as a pivotal factor in angiogenesis and is a potential target for neoplasm therapy.

Beta-Sitosterol Promotes Milk Protein and Fat Syntheses-Related Genes in Bovine Mammary Epithelial Cells

“…β-sitosterol attenuates insulin resistance by reducing insulin receptor substrate-1 (IRS-1) serine phosphorylation and activating downstream signaling molecules in rats [ 41 ]. Studies postulate that insulin stimulates HIF-1α [ 42 ], a nuclear transcription factor activated under hypoxic conditions, in a concentration-dependent manner [ 43 ]. Notably, it regulates a series of hypoxia signal pathways to enhance the expression of erythropoietin (EPO) and its receptor (erythropoietin receptor, EPOR) genes [ 44 ], thereby promoting the proliferation and differentiation of mammalian erythroid progenitor cells.…”

Cardiovascular disease associated with radiotherapy: activation of nuclear factor kappa-B

“…The authors suggested that anti‐VEGF medication should be investigated for use in other types of radiation vasculopathy. This is interesting because VEGF seems to play a pivotal role in disruption of the integrity of the vessel wall during inflammation [83], and NF‐κB activates VEGF expression [83, 84] whereas inhibition of NF‐κB decreases levels of VEGF [85].…”

The Candidate Tumor Suppressor Gene SLC8A2 Inhibits Invasion, Angiogenesis and Growth of Glioblastoma

“…Our study found that SLC8A2 inhibited migration, invasion, and the tube formation of endothelial cells, as well as down-regulated the expression of VEGF189, VEGF165, and VEGF121. In addition, COX-2 and HIF-1α, tumor angiogenesis-related genes which can regulate VEGF expression ( Kimba et al, 2005 ), were also suppressed by SLC8A2 overexpression. These results suggested that SLC8A2 inhibited endothelium-dependent angiogenesis of glioblastoma.…”