title: 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: Department of Obstetrics and Gynecology, Hallym University, Seoul 150‑950, Republic of Korea.
authors: Sung Taek
authors: ST
authors: Park
authors: Research Institute, National Cancer Center, Goyang-si, Gyeonggi‑do 410‑769, Republic of Korea.
authors: Boh-Ram
authors: BR
authors: Kim
authors: Department of Obstetrics and Gynecology, Hallym University, Seoul 150‑950, Republic of Korea.
authors: Sung Ho
authors: SH
authors: Park
authors: Department of Obstetrics and Gynecology, Chonbuk National University Medical School, Jeonju 561‑712, Republic of Korea.
authors: Jeong Heon
authors: JH
authors: Lee
authors: Department of Obstetrics and Gynecology, Chung‑Ang University School of Medicine/Chung‑Ang University Hospital, Seoul 156-755, Republic of Korea.
authors: Eun-Ju
authors: EJ
authors: Lee
authors: Department of Life Science, Yong In University, Yongin-si, Gyeonggi-do 449-714, Republic of Korea.
authors: Seung-Hoon
authors: SH
authors: Lee
authors: Research Institute, National Cancer Center, Goyang-si, Gyeonggi‑do 410‑769, Republic of Korea.
authors: Seung Bae
authors: SB
authors: Rho
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D064550:Death-Associated Protein Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D064550:Death-Associated Protein Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C000588866:KDR protein, human