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Androgen receptor expression in prostate carcinoma cells suppresses alpha6beta4 integrin-mediated invasive phenotype
L Bonaccorsi1, V Carloni, M Muratori
1Department of Clinical Physiopathology, University of Florence, Italy.
Abstract:
Prostate cancer cells may lose androgen-sensitivity after androgen ablation therapy, becoming highly invasive and metastatic. The biological mechanisms responsible for higher tumurogenicity of androgen-independent prostate carcinomas are not entirely known. We demonstrate that androgen receptor regulation of adhesion and invasion of prostate cancer cells through modulation of alpha6beta4 integrin expression may be one of the molecular mechanisms responsible of this phenomenon. We found that protein and gene expressions of alpha6 and beta4 subunits were strongly reduced in the androgen-sensitive cell line LNCaP respect to the androgen-independent PC3 and that transfection of PC3 cells with a full-length androgen receptor expression vector resulted in a decreased expression of alpha6beta4 integrin, reduced adhesion on laminin, and suppressed Matrigel invasion. Growth in soft agar was also suppressed in androgen receptor-positive PC3 clones. Treatment of androgen receptor positive clones with the synthetic androgen R1881 further reduced alpha6 and beta4 messenger RNA expression as well as adhesion on laminin and Matrigel invasion. Our results indicate that androgens regulate cell-extracellular matrix adhesion and invasion by modulation of integrin expression and function, thus keeping a low invasive phenotype of prostate cancer cells.
Insights
Androgen receptor signaling in prostate cancer cells regulates cell adhesion and invasion by modulating alpha6beta4 integrin expression. This mechanism helps maintain a less invasive tumor phenotype.
Area of Science:
- Integrative Biology
- Molecular Oncology
- Cellular Biology
Background:
- Prostate cancer can become androgen-independent and highly invasive after androgen ablation therapy.
- The underlying biological mechanisms driving increased tumurogenicity in androgen-independent prostate cancer are not fully understood.
Purpose of the Study:
- To investigate the role of androgen receptor (AR) signaling in regulating prostate cancer cell adhesion and invasion.
- To explore the potential involvement of alpha6beta4 integrin in AR-mediated modulation of prostate cancer cell invasiveness.
Main Methods:
- Comparative analysis of alpha6 and beta4 integrin subunit expression in androgen-sensitive (LNCaP) versus androgen-independent (PC3) prostate cancer cell lines.
- Transfection of PC3 cells with an AR expression vector to assess changes in integrin expression, adhesion, and invasion.
- Treatment of AR-positive PC3 clones with synthetic androgen (R1881) to evaluate effects on gene expression and cellular behavior.
- Soft agar assays to assess anchorage-independent growth.
Main Results:
- Alpha6 and beta4 integrin expression was significantly lower in androgen-sensitive LNCaP cells compared to androgen-independent PC3 cells.
- AR re-expression in PC3 cells led to decreased alpha6beta4 integrin expression, reduced adhesion to laminin, and suppressed Matrigel invasion.
- AR-positive PC3 clones exhibited suppressed growth in soft agar.
- Androgen treatment (R1881) further reduced alpha6 and beta4 mRNA levels, laminin adhesion, and Matrigel invasion in AR-positive PC3 cells.
Conclusions:
- Androgen receptor signaling directly modulates the expression and function of alpha6beta4 integrin in prostate cancer cells.
- Regulation of cell-extracellular matrix adhesion and invasion via integrin modulation by androgens is a key mechanism contributing to a less invasive phenotype in prostate cancer.