Ellagic acid inhibits VEGF/VEGFR2, PI3K/Akt and MAPK signaling cascades in the hamster cheek pouch carcinogenesis model
| Autor: | Madhulika Dixit, Raju Naik Vankudavath, Tanagala Kranthi Kiran Kishore, Geereddy Bhanuprakash Reddy, Hemant Giri, Rushendhiran Kesavan, Siddavaram Nagini, Jaganathan Kowshik |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Male Vascular Endothelial Growth Factor A Cancer Research Angiogenesis Carcinogenesis 9 10-Dimethyl-1 2-benzanthracene Angiogenesis Inhibitors Biology Histone Deacetylases Cell Line chemistry.chemical_compound Phosphatidylinositol 3-Kinases Ellagic Acid Cell Line Tumor Animals Protein kinase B PI3K/AKT/mTOR pathway Pharmacology Mesocricetus Neovascularization Pathologic Kinase Endothelial Cells Vascular Endothelial Growth Factor Receptor-2 Cell Hypoxia Cell biology Vascular endothelial growth factor Molecular Docking Simulation Oncogene Protein v-akt Cheek chemistry Molecular Medicine Signal transduction Mitogen-Activated Protein Kinases Ellagic acid Signal Transduction |
| Zdroj: | Anti-cancer agents in medicinal chemistry. 14(9) |
| ISSN: | 1875-5992 |
| Popis: | 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. General Significance: Ellagic acid offers promise as a lead compound for anticancer therapeutics by virtue of its ability to inhibit key oncogenic signaling cascades and HDACs. |
| Databáze: | OpenAIRE |
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