title: Ellagic acid inhibits VEGF/VEGFR2, PI3K/Akt and MAPK signaling cascades in the hamster cheek pouch carcinogenesis model.
abstract: BACKGROUND
  Blocking vascular endothelial growth factor (VEGF) mediated tumor angiogenesis by phytochemicals has emerged as an attractive strategy for cancer prevention and therapy.
  
  
  METHODS
  We investigated the anti-angiogenic effects of ellagic acid in a hamster model of oral oncogenesis by examining the transcript and protein expression of hypoxia-inducible factor-1alpha (HIF-1α), VEGF, VEGFR2, and the members of the PI3K/Akt and MAPK signaling cascades. Molecular docking studies and cell culture experiments with the endothelial cell line ECV304 were performed to delineate the mechanism by which ellagic acid regulates VEGF signaling.
  
  
  RESULTS
  We found that ellagic acid significantly inhibits HIF-1α-induced VEGF/VEGFR2 signalling in the hamster buccal pouch by abrogating PI3K/Akt and MAPK signaling via downregulation of PI3K, PDK-1, p-Akt(ser473), mTOR, p-ERK, and p-JNK. Ellagic acid was also found to reduce the expression of histone deacetylases that could inhibit neovascularization. Analysis of the mechanism revealed that ellagic acid inhibits hypoxia-induced angiogenesis via suppression of HDAC-6 in ECV304 cells. Furthermore, knockdown of endogenous HDAC6 via small interfering RNA abrogated hypoxia-induced expression of HIF-1α and VEGF and blocked Akt activation. Molecular docking studies confirmed interaction of ellagic acid with upstream kinases that regulate angiogenic signaling.
  
  
  CONCLUSIONS
  Taken together, these findings demonstrate that the anti-angiogenic activity of ellagic acid may be mediated by abrogation of hypoxia driven PI3K/Akt/mTOR, MAPK and VEGF/VEGFR2 signaling pathways involving suppression of HDAC6 and HIF-1α responses.
  
  
  CONCLUSIONS
  Ellagic acid offers promise as a lead compound for anticancer therapeutics by virtue of its ability to inhibit key oncogenic signaling cascades and HDACs.
authors: Jaganathan
authors: J
authors: Kowshik
authors: Hemant
authors: H
authors: Giri
authors: Tanagala Kranthi Kiran
authors: TK
authors: Kishore
authors: Rushendhiran
authors: R
authors: Kesavan
authors: Raju Naik
authors: RN
authors: Vankudavath
authors: Geereddy Bhanuprakash
authors: GB
authors: Reddy
authors: Madhulika
authors: M
authors: Dixit
authors: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar- 608 002, Tamil Nadu, India. s_nagini@yahoo.com.
authors: Siddavaram
authors: S
authors: Nagini
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002610:Cheek / Q000473:pathology; D004610:Ellagic Acid / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D004610:Ellagic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases