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Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells
Michael E Wright1, Ming-Jer Tsai, Ruedi Aebersold
1Institute for Systems Biology, Seattle, Washington 98103, USA. mwright@systemsbiology.org.
Abstract:
Androgen-ablation therapy is an effective method for treating prostate cancer. However, prostate tumors that survive long-term androgen-ablation therapy are classified as androgen-independent as they proliferate in the absence of androgens, and they tend to be enriched for neuroendocrine (NE) cells. Androgen withdrawal causes androgen-dependent prostate cancer cells to adopt a pronounced NE phenotype, suggesting that androgen receptor (AR) represses an intrinsic NE transdifferentiation process in prostate cancer cells. In this report we show that short interfering RNA-induced AR silencing induced a NE phenotype that manifested itself in the growth of dendritic-like processes in both the androgen-dependent LNCaP and androgen-independent LNCaP-AI human prostate cancer cells. Western blot analysis revealed that neuronal-specific enolase, a marker of the neuronal lineage, was increased by AR knockdown in LNCaP cells. The expression levels of the neuronal-specific cytoskeletal proteins beta-tubulin III, nestin, and glial acidic fibrillary protein were also characterized in AR knockdown cells. Most interestingly, AR silencing induced beta-tubulin III expression in LNCaP cells, while AR knockdown increased glial acidic fibrillary protein levels in both LNCaP and LNCaP-AI cells. Lastly, AR silencing reduced the proliferative capacity of LNCaP and LNCaP-AI cells. Our data demonstrate that AR actively represses an intrinsic NE transdifferentiation process in androgen-responsive prostate cancer cells and suggest a potential link between AR inactivation and the increased frequency of NE cells in androgen-independent tumors.
Insights
Androgen receptor (AR) actively suppresses neuroendocrine (NE) transdifferentiation in prostate cancer cells. Silencing AR promotes NE cell characteristics and reduces tumor proliferation, suggesting AR
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Androgen-ablation therapy is a standard treatment for prostate cancer.
- Prostate tumors can become androgen-independent and enriched for neuroendocrine (NE) cells.
- Androgen withdrawal induces a NE phenotype in prostate cancer cells, suggesting AR repression of NE transdifferentiation.
Purpose of the Study:
- To investigate the role of the androgen receptor (AR) in repressing neuroendocrine (NE) transdifferentiation in prostate cancer cells.
- To determine the effect of AR silencing on NE cell markers and proliferation in both androgen-dependent and independent prostate cancer cells.
Main Methods:
- Utilized short interfering RNA (siRNA) to silence androgen receptor (AR) expression in LNCaP and LNCaP-AI human prostate cancer cells.
- Assessed the induction of NE phenotype by examining dendritic-like process growth.
- Analyzed the expression of NE markers (neuronal-specific enolase, beta-tubulin III, nestin, glial acidic fibrillary protein) using Western blot.
- Evaluated the proliferative capacity of AR-silenced cells.
Main Results:
- AR silencing induced a neuroendocrine (NE) phenotype, including dendritic-like process formation, in both androgen-dependent and independent prostate cancer cells.
- AR knockdown increased the expression of neuronal markers like neuronal-specific enolase and beta-tubulin III.
- AR silencing reduced the proliferative capacity of prostate cancer cells.
Conclusions:
- Androgen receptor (AR) actively represses an intrinsic neuroendocrine (NE) transdifferentiation process in androgen-responsive prostate cancer cells.
- AR inactivation may be linked to the increased frequency of NE cells observed in androgen-independent prostate tumors.
- Targeting AR could be a strategy to modulate NE transdifferentiation in prostate cancer.