title: Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells.
abstract: Neuroendocrine (NE) cells are the minor cell populations in normal prostate epithelial compartments. During prostate carcinogenesis, the number of NE cells in malignant lesions increases, correlating with its tumorigenicity and hormone-refractory growth. It is thus proposed that cancerous NE cells promote prostate cancer (PCa) cell progression and its androgen-independent proliferation, although the origin of the cancerous NE cells is not clear. To investigate the role of cancerous NE cells in prostate carcinogenesis, we characterized three NE subclone cell lines-NE-1.3, NE-1.8 and NE-1.9, which were transdifferentiated from androgen-sensitive human PCa LNCaP cells by culturing in an androgen-depleted environment, resembling clinical androgen-ablation therapy. These subclone cells acquire many features of NE cells seen in clinical prostate carcinomas, for example exhibiting a neuronal morphology and expressing multiple NE markers, including neuron-specific enolase, chromogranin B, neurotensin, parathyroid hormone-related peptide, and to a lesser degree for chromogranin A, while lacking androgen receptor (AR) or prostate specific antigen (PSA) expression. These cells represent terminally differentiated stable cells because after 3 months of re-culturing in a medium containing androgenic activity, they still retained the NE phenotype and expressed NE markers. Despite these NE cells having a slow growth rate, they readily developed xenograft tumors. Furthermore, media conditioned by these NE cells exhibited a stimulatory effect on proliferation and PSA secretion by LNCaP cells in androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase alpha plays a role in upregulating multiple NE markers and acquiring the NE phenotype. These NE cells thus represent cancerous NE cells and could serve as a useful cell model system for investigating the role of cancerous NE cells in hormone-refractory proliferation of PCa cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Ta-Chun
authors.initials: TC
authors.lastname: Yuan
authors.forename: Suresh
authors.initials: S
authors.lastname: Veeramani
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Lin
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kondrikou
authors.forename: Stanislav
authors.initials: S
authors.lastname: Zelivianski
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Igawa
authors.forename: Dev
authors.initials: D
authors.lastname: Karan
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000728:Androgens / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009496:Neurotensin / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011944:Receptors, Androgen / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000728:Androgens; D053379:Chromogranin A; D002864:Chromogranins; D044162:Parathyroid Hormone-Related Protein; D011944:Receptors, Androgen; D011956:Receptors, Cell Surface; D009496:Neurotensin; C516841:PTPRA protein, human; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D017430:Prostate-Specific Antigen; D010751:Phosphopyruvate Hydratase