Abstract
In this study we describe a novel Rho small GTPase dependent pathway that elicits apoptotic responses controlled by actin reorganization in hormone-sensitive LNCaP- and hormone insensitive DU145-prostate cancer cells stimulated with membrane androgen receptor selective agonists. Using an albumin-conjugated steroid, testosterone-BSA, we now show significant induction of actin polymerization and apoptosis that can be reversed by actin disrupting agents in both cell lines. Testosterone-BSA triggered RhoA/B and Cdc42 activation in DU145 cells followed by stimulation of downstream effectors ROCK, LIMK2 and ADF/destrin. Furthermore, dominant-negative RhoA, RhoB or Cdc42 mutants or pharmacological inhibitors of ROCK inhibited both actin organization and apoptosis in DU145 cells. Activation of RhoA/B and ROCK was also implicated in membrane androgen receptor-dependent actin polymerization and apoptosis in LNCaP cells. Our findings suggest that Rho small GTPases are major membrane androgen receptor effectors controlling actin reorganization and apoptosis in prostate cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism*
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Amides / metabolism
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Animals
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Apoptosis / physiology*
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Cell Line, Tumor
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Destrin / metabolism
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Enzyme Activation
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Enzyme Inhibitors / metabolism
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / metabolism
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Humans
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Lim Kinases / metabolism
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Male
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Pyridines / metabolism
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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Serum Albumin, Bovine / metabolism
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Signal Transduction / physiology*
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Testosterone / analogs & derivatives
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Testosterone / metabolism
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cdc42 GTP-Binding Protein / metabolism
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rac1 GTP-Binding Protein / metabolism
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism*
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
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rhoB GTP-Binding Protein / genetics
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rhoB GTP-Binding Protein / metabolism*
Substances
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Actins
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Amides
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DSTN protein, human
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Destrin
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Enzyme Inhibitors
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Pyridines
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Receptors, Androgen
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testosterone-3-carboxymethyloxime-bovine serum albumin conjugate
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Y 27632
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Serum Albumin, Bovine
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Testosterone
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Phosphatidylinositol 3-Kinases
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Focal Adhesion Kinase 1
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PTK2 protein, human
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LIMK2 protein, human
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Lim Kinases
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rho-Associated Kinases
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cdc42 GTP-Binding Protein
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein
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rhoB GTP-Binding Protein