title: 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.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Mounia
authors.initials: M
authors.lastname: Guerram
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Chongchong
authors.initials: C
authors.lastname: Tian
authors.affiliation: Medical and Chemical Institute, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.|Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, P.R. China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D003599:Cytoskeleton / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D004365:Drugs, Chinese Herbal; D047428:Protein Kinase Inhibitors; C066737:RHOA protein, human; C014451:deoxypodophyllotoxin; D040301:Vascular Endothelial Growth Factor Receptor-2; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D011034:Podophyllotoxin
keywords: AMP-activated protein kinase; Rho A; cytoskeleton remodeling; deoxypodophyllotoxin; tumor vasculature