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PMID: 18079321 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Ligand-independent activation of androgen receptors by Rho GTPase signaling in prostate cancer.

Molecular endocrinology (Baltimore, Md.) ·Vol. 22 ·No. 3 ·2008-03-00 ·Pages 597-608

Lyons LS, Rao S, Balkan W, Faysal J, Maiorino CA, Burnstein KL

Abstract

Prostate cancer invariably recurs after androgen deprivation therapy. Growth of this recurrent/androgen-independent form of prostate cancer may be due to increased androgen receptor (AR) transcriptional activity in the absence of androgen. This ligand-independent AR activation is promoted by some growth factors but the mechanism is not well understood. Vav3, a Rho guanosine triphosphatase guanine nucleotide exchange factor, which is activated by growth factors, is up-regulated in human prostate cancer. We show here that Vav3 levels increase during in vivo progression of prostate cancer to androgen independence. Vav3 strikingly enhanced growth factor activation of AR in the absence of androgen. Because Vav3 may be chronically activated in prostate cancer by growth factor receptors, we examined the effects of a constitutively active (Ca) form of Vav3 on AR transcriptional activity. Ca Vav3 caused nuclear localization and ligand-independent activation of AR via the Rho guanosine triphosphatase, Rac1. Ca Rac1 activation of AR occurred, in part, through MAPK/ERK signaling. Expression of active Rac1 conferred androgen-independent growth of prostate cancer cells in culture, soft agar, and mice. These findings suggest that Vav3/Rac 1 signaling is an important modulator of ligand-independent AR transcriptional activity in prostate cancer progression.

MeSH Terms
Animals Cell Line, Tumor Guanine Nucleotide Exchange Factors/biosynthesis,genetics,metabolism Humans MAP Kinase Signaling System Male Mice Mice, Nude Mitogen-Activated Protein Kinases/metabolism Neoplasm Transplantation Neoplasms, Hormone-Dependent/enzymology,metabolism Prostatic Neoplasms/enzymology,metabolism Proto-Oncogene Proteins c-vav/biosynthesis,genetics,metabolism RNA, Messenger/biosynthesis,genetics Receptors, Androgen/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Transcription, Genetic Transplantation, Heterologous Up-Regulation rac1 GTP-Binding Protein/biosynthesis,genetics,metabolism
Chemicals
AR protein, human Guanine Nucleotide Exchange Factors Proto-Oncogene Proteins c-vav RAC1 protein, human RNA, Messenger Receptors, Androgen VAV3 protein, human Mitogen-Activated Protein Kinases rac1 GTP-Binding Protein
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Lyons Leah S
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Rao Shuyun
Balkan Wayne
Faysal Joanne
Maiorino Carol A
Burnstein Kerry L
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Article Info
Journal
Molecular endocrinology (Baltimore, Md.)
Abbr.
Mol Endocrinol
ISSN
0888-8809
DOI
10.1210/me.2007-0158
Published
2008-03-00
Epub
2007-00-13
Pages
597-608
Language
English
Region
United States
NLM ID
8801431
PMCID
PMC2262175
Subset
IM
Grants
NIDDK NIH HHS · R21 DK065281 · United States
NIDDK NIH HHS · DK065281 · United States
External Links
PubMed source DOI: 10.1210/me.2007-0158 PMC Full Text View journal details
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