title: Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells.
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.
authors.affiliation: Institute for Systems Biology, Seattle, Washington 98103, USA. mwright@systemsbiology.org.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Wright
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
mesh_terms: D015415:Biomarkers; D002277:Carcinoma / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008297:Male; D009490:Neurosecretory Systems / Q000378:metabolism*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D015415:Biomarkers; D034741:RNA, Small Interfering; D011944:Receptors, Androgen