Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio.

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.

• Authors: Yurong Wang, Bin Wang, Mounia Guerram, Li Sun, Wei Shi, Chongchong Tian, Xiong Zhu, Zhenzhou Jiang, Luyong Zhang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 30 Pg. 29497-512 (Oct 06 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26470595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Drugs, Chinese Herbal
• Protein Kinase Inhibitors
• RHOA protein, human
• deoxypodophyllotoxin
• Vascular Endothelial Growth Factor Receptor-2
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• rhoA GTP-Binding Protein
• Podophyllotoxin

Topics

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Animals, Genetically Modified
• Cytoskeleton (drug effects, enzymology)
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal
• Enzyme Activation
• Female
• HeLa Cells
• Human Umbilical Vein Endothelial Cells (drug effects, enzymology)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic
• Neovascularization, Physiologic (drug effects)
• Podophyllotoxin (analogs & derivatives, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Interference
• Signal Transduction (drug effects)
• Stomach Neoplasms (blood supply, drug therapy, enzymology, genetics, pathology)
• Time Factors
• Transfection
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)
• Xenograft Model Antitumor Assays
• Zebrafish (genetics, metabolism)
• rhoA GTP-Binding Protein (genetics, metabolism)