Androgen-Induced Cell Migration: Role of Androgen Receptor/Filamin A Association
Open Access
- 16 February 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (2), e17218
- https://doi.org/10.1371/journal.pone.0017218
Abstract
Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK), paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development and prostate cancer metastasis.This publication has 61 references indexed in Scilit:
- Analysis and modelling of motility of cell populations with MotoCellBMC Bioinformatics, 2009
- Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptorThe Journal of Experimental Medicine, 2009
- p21-Activated kinase mediates rapid estradiol-negative feedback actions in the reproductive axisProceedings of the National Academy of Sciences of the United States of America, 2009
- Nuclear versus Cytoplasmic Localization of Filamin A in Prostate Cancer: Immunohistochemical Correlation with MetastasesClinical Cancer Research, 2009
- Targeting the stromal androgen receptor in primary prostate tumors at earlier stagesProceedings of the National Academy of Sciences of the United States of America, 2008
- Paxillin comes of ageJournal of Cell Science, 2008
- Extra-Nuclear Signaling of Progesterone Receptor to Breast Cancer Cell Movement and Invasion through the Actin CytoskeletonPLOS ONE, 2008
- Hormone-dependent nuclear export of estradiol receptor and DNA synthesis in breast cancer cellsThe Journal of cell biology, 2008
- Focal adhesion kinase: in command and control of cell motilityNature Reviews Molecular Cell Biology, 2005
- FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassemblyNature, 2004