Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite

Abstract

Recently we have demonstrated that sodium arsenite induces the expression of hypoxia-inducible factor 1␣ (HIF-1␣) protein and vascular endothelial growth factor (VEGF) in OVCAR-3 human ovarian cancer cells. We now show that arsenic trioxide, an experimental anticancer drug, exerts the same effects. The involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) pathways in the effects of sodium arsenite was investigated. By using kinase inhibitors in OVCAR-3 cells, both effects of sodium arsenite were found to be independent of phosphatidylinositol 3-kinase and p44/p42 MAPKS but were attenuated by inhibition of p38 MAPK. A role for p38 in the regulation of HIF-1␣ and VEGF expression was supported further by analysis of activation kinetics. Experiments in mouse fibroblast cell lines, lacking expression of c-Jun N-terminal kinases 1 and 2, suggested that these kinases are not required for induction of HIF-1␣ protein and VEGF mRNA. Unexpectedly, sodium arsenite did not activate a HIF-1-dependent reporter gene in OVCAR-3 cells, indicating that functional HIF-1 was not induced. In agreement with this hypothesis, up-regulation of VEGF mRNA was not reduced in HIF-1␣ ؊/؊ mouse fibroblast cell lines. Altogether, these data suggest that not HIF-1, but rather p38, mediates induction of VEGF mRNA expression by sodium arsenite.

Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes

“…There are many reports that Ang-II activates p38 MAPK in various kinds of cells including mesangial cells (Reddy et al 2002) and vascular smooth muscle cells (Touyz et al 2001). There is now a wealth of data supporting a direct role for p38 MAPK as a signaling pathway in the production of VEGF (Tanaka et al 2000, Jung et al 2001, Duyndam et al 2003, Tokuda et al 2003, Tsai et al 2003. Therefore, in this study, we focused on the p38 MAPK pathway to identify the signaling pathways that mediate Ang-II-induced VEGF synthesis.…”

Signal Pathway of Hypoxia-Inducible Factor-1α Phosphorylation and its Interaction with von Hippel-Lindau Tumor Suppressor Protein During Ischemia in MiaPaCa-2 Pancreatic Cancer Cells

“…Several MAPKs have been reported to cause the phosphorylation of HIF-1a, which results in the activation and stabilization of HIF-1a (9). The p38 MAPK among several MAPKs is required for stabilization of HIF-1a induced by Cr(VI) and sodium arsenite (24,25). In addition, the fusion protein with glutathione S-transferase and transactivation domain of HIF-1a is directly phosphorylated in vitro by activated p38a and p38g MAPK resulting in the stimulation of transactivating activity of HIF-1a (26).…”

Mitogen-Activated Protein 3 Kinase 6 Mediates Angiogenic and Tumorigenic Effects via Vascular Endothelial Growth Factor Expression

“…Although several groups have reported the participation of the JNK/ERK/p38 pathways in VEGF expression, [37][38][39][40][41] it remains unknown whether MAP3K6 plays a role in these pathways. MAP3K6 was originally identified as a member of the serine/threonine protein kinase family by its interaction with MAP3K5/ASK1, a protein kinase that also activates c-Jun kinase (JNK) and p38 kinase.…”