PUBLICATION
Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio
- Authors
- Wang, Y., Wang, B., Guerram, M., Sun, L., Shi, W., Tian, C., Zhu, X., Jiang, Z., Zhang, L.
- ID
- ZDB-PUB-151019-18
- Date
- 2015
- Source
- Oncotarget 6: 29497-512 (Journal)
- Registered Authors
- Keywords
- AMP-activated protein kinase, Rho A, cytoskeleton remodeling, deoxypodophyllotoxin, tumor vasculature
- MeSH Terms
-
- AMP-Activated Protein Kinases/antagonists & inhibitors
- AMP-Activated Protein Kinases/genetics
- AMP-Activated Protein Kinases/metabolism*
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Animals, Genetically Modified
- Cytoskeleton/drug effects*
- Cytoskeleton/enzymology
- Dose-Response Relationship, Drug
- Enzyme Activation
- Female
- HeLa Cells
- Human Umbilical Vein Endothelial Cells/drug effects*
- Human Umbilical Vein Endothelial Cells/enzymology
- Humans
- Mice, Inbred BALB C
- Mice, Nude
- Neovascularization, Pathologic*
- Neovascularization, Physiologic/drug effects
- Podophyllotoxin/analogs & derivatives*
- Podophyllotoxin/pharmacology
- Protein Kinase Inhibitors/pharmacology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- RNA Interference
- Signal Transduction/drug effects*
- Stomach Neoplasms/blood supply
- Stomach Neoplasms/drug therapy*
- Stomach Neoplasms/enzymology
- Stomach Neoplasms/genetics
- Stomach Neoplasms/pathology
- Time Factors
- Transfection
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Xenograft Model Antitumor Assays
- Zebrafish/genetics
- Zebrafish/metabolism
- rhoA GTP-Binding Protein/genetics
- rhoA GTP-Binding Protein/metabolism*
- PubMed
- 26470595 Full text @ Oncotarget
Citation
Wang, Y., Wang, B., Guerram, M., Sun, L., Shi, W., Tian, C., Zhu, X., Jiang, Z., Zhang, L. (2015) Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio. Oncotarget. 6:29497-512.
Abstract
Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping