Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 40, Pages E2665-E2674Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206036109
Keywords
high-content screening; small compound screening; lymphatic endothelium; chemical genetics
Categories
Funding
- National Institutes of Health Grant [CA69184, EY017392]
- Swiss National Science Foundation [3100A0-108207, 31003A-130627, 205321-134783]
- European Communities [LSHC-CT-2005-518178]
- European Research Council [LYVICAM]
- Deutsche Forschungsgemeinschaft [FOR1406, TP4]
- Oncosuisse
- Krebsliga Zurich
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Lymphangiogenesis plays an important role in promoting cancer metastasis to sentinel lymph nodes and beyond and also promotes organ transplant rejection. We used human lymphatic endothelial cells to establish a reliable three-dimensional lymphangiogenic sprouting assay with automated image acquisition and analysis for inhibitor screening. This high-content phenotype-based assay quantifies sprouts by automated fluorescence microscopy and newly developed analysis software. We identified signaling pathways involved in lymphangiogenic sprouting by screening the Library of Pharmacologically Active Compounds (LOPAC)(1280) collection of pharmacologically relevant compounds. Hit characterization revealed that mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors substantially block lymphangiogenesis in vitro and in vivo. Importantly, the drug class of statins, for the first time, emerged as potent inhibitors of lymphangiogenic sprouting in vitro and of corneal and cutaneous lymphangiogenesis in vivo. This effect was mediated by inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and subsequently the isoprenylation of Rac1. Supplementation with the enzymatic products of HMG-CoA reductase functionally rescued lymphangiogenic sprouting and the recruitment of Rac1 to the plasma membrane.
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