Suppression of VEGF expression through interruption of the HIF-1α and Akt signaling cascade modulates the anti-angiogenic activity of DAPK in ovarian carcinoma cells

Abstract

Death-associated protein kinase (DAPK) plays an important role in apoptosis regulation and has been shown to maintain antitumor and metastasis suppressor properties. In the present study, we investigated whether DAPK over-expression may mediate vascular endothelial growth factor (VEGF)/hypoxia-inducible factor-1α (HIF-1α) expression and angiogenic activity in the human carcinoma cell model system. VEGF plays a pivotal role in tumor angiogenesis and tumorigenesis. We found that DAPK significantly downregulated VEGF-induced endothelial cell proliferation, migration and tube formation as well as VEGF receptor-2 (VEGFR-2) phosphorylation in vitro. In addition, DAPK exhibited potent anti-angiogenic activity and clearly decreased the levels of VEGF and HIF-1α expression, a key regulator for angiogenesis. Notably, our results strongly indicated that DAPK can disturb VEGFR-2 transcriptional activity by inhibiting VEGFR-2 phosphorylation through the PI3K/Akt signaling cascade. Collectively, our study identified a novel function of DAPK in regulating cellular VEGF/HIF-1α activity during tumorigenesis, which may act together with its anti-angiogenic function to inhibit tumor progression.