Abstract
The Rho-kinase inhibitor, Y-27632, inhibited in vitro chemotactic migration to bone marrow fibroblast conditioned media and metastatic growth in immune-compromised mice of highly invasive human prostatic cancer (PC3) cells. Y-27632 also reduced myosin light chain phosphorylation and markedly altered the morphology of cells that developed numerous processes containing microtubules. A strikingly different, rounded phenotype was induced by an inhibitor of myosin light chain kinase, ML9. The M(110-130) subunit of the myosin phosphatase that is regulated by Rho-kinase was present in PC3 cells that contained significantly more RhoA than the less invasive, LNCaP cells. Y-27632 also inhibited angiogenesis as measured by endothelial cell tube formation on Matrigel. We conclude that invasiveness of human prostate cancer is facilitated by the Rho/Rho-kinase pathway, and exploration of selective Rho-kinase inhibitors for limiting invasive progress of prostate cancer is warranted.
Copyright 2000 Academic Press.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amides / pharmacology*
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Animals
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Azepines / pharmacology*
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Cattle
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Cell Division / drug effects
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Cells, Cultured
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Chemotaxis / drug effects
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / physiology
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Enzyme Inhibitors / pharmacology
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Humans
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Intracellular Signaling Peptides and Proteins
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Male
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Mice
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Mice, Transgenic
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Myosin-Light-Chain Kinase / antagonists & inhibitors
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Myosin-Light-Chain Phosphatase
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Neoplasm Invasiveness / prevention & control
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Neoplasm Metastasis / prevention & control
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Neovascularization, Physiologic / drug effects
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Prostatic Neoplasms / pathology*
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Prostatic Neoplasms / physiopathology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyridines / pharmacology*
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Transplantation, Heterologous
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Tumor Cells, Cultured
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rho-Associated Kinases
Substances
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Amides
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Azepines
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Pyridines
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ML 9
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Y 27632
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Myosin-Light-Chain Kinase
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Phosphoprotein Phosphatases
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Myosin-Light-Chain Phosphatase