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 overexpression 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.

• Authors: Sung Taek Park, Boh-Ram Kim, Sung Ho Park, Jeong Heon Lee, Eun-Ju Lee, Seung-Hoon Lee, Seung Bae Rho
• Journal: Oncology reports (Oncol Rep) Vol. 31 Issue 2 Pg. 1021-9 (Feb 2014) ISSN: 1791-2431 [Electronic] Greece
• PMID: 24337450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2
• Death-Associated Protein Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Angiogenesis Inhibitors (genetics)
• Cell Hypoxia
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics)
• Death-Associated Protein Kinases (biosynthesis, genetics, metabolism)
• Female
• HEK293 Cells
• Human Umbilical Vein Endothelial Cells (pathology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, biosynthesis, genetics)
• Neovascularization, Pathologic (pathology)
• Ovarian Neoplasms (genetics, pathology)
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (genetics)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, physiology)
• RNA Interference
• RNA, Small Interfering
• Signal Transduction
• Transcription, Genetic
• Transcriptional Activation
• Vascular Endothelial Growth Factor A (biosynthesis, genetics)
• Vascular Endothelial Growth Factor Receptor-1 (genetics)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)