Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells.

Wright, Michael E.; Tsai, Ming-Jer; Aebersold, Ruedi

doi:10.1210/me.2003-0031

Cited by 166Prostate Cancer Treatment and ResearchEstrogen and related hormone effectsSperm and Testicular Function

Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells.

Open access

Wright, Michael E., Tsai, Ming-Jer, Aebersold, Ruedi·2003·Molecular Endocrinology

DOI 10.1210/me.2003-0031

Open this paper in CoChat — free account Open PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1210/me.2003-0031

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Silencing of AR in LNCaP cells results in a shift to a more neuroendocrine-like phenotype.
“The AR may be a critical factor in maintaining epithelial-like characteristics in tumor cells, because silencing of AR in LNCaP cells results in a shift to a more NE-like phenotype (39).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [39]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001) · Nature · doi:10.1038/35078107 · Cited by 9,456 · see citing works
Culture of Animal Cells
Freshney, R. I. (2005) · Wiley eBooks · doi:10.1002/9780470649367 · Cited by 3,869 · see citing works
CNS stem cells express a new class of intermediate filament protein
Lendahl, U., Zimmerman, L. B., & McKay, R. D. G. (1990) · Cell · doi:10.1016/0092-8674(90)90662-x · Cited by 3,164 · see citing works
Studies on Prostatic Cancer: I. The Effect of Castration, Of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate
Huggins, C. E., & Hodges, C. V. (1972) · CA A Cancer Journal for Clinicians · doi:10.3322/canjclin.22.4.232 · Cited by 1,322 · see citing works
Culture of Animal Cells: A Manual of Basic Technique
Tee, D. E. H. (1985) · Food and Chemical Toxicology · doi:10.1016/0278-6915(85)90082-1 · Cited by 1,256 · see citing works
Molecular Biology of the Androgen Receptor
Gelmann, E. P. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.10.018 · Cited by 944 · see citing works
Molecular genetics of prostate cancerPreprint
Abate-Shen, C. T., & Shen, M. M. (2000) · Genes & Development · doi:10.1101/gad.819500 · Cited by 740 · see citing works
Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes
Eng, L. F. (1985) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(85)80063-1 · Cited by 737 · see citing works
Biology of Prostate-Specific Antigen
Balk, S. P., Ko, Y.-J., & Bubley, G. J. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.02.083 · Cited by 730 · see citing works
Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors
Zimmerman, L. B., Lendahl, U., Cunningham, M. G., McKay, R. D. G., Parr, B. A., Gavin, B. J., Mann, J. R., Vassileva, G., & McMahon, A. P. (1994) · Neuron · doi:10.1016/0896-6273(94)90148-1 · Cited by 583 · see citing works
RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans
Montgomery, M. K., Xu, S., & Fire, A. Z. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15502 · Cited by 580 · see citing works
Proliferation and differentiation of rat neuroepithelial precursor cells in vivo
Frederiksen, K., & McKay, R. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-04-01144.1988 · Cited by 560 · see citing works
Untitled work
(2001) · PubMed · Cited by 500 · see citing works
Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones.
Kemppainen, J., Lane, M. V., Sar, M., & Wilson, E. M. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)48380-9 · Cited by 430 · see citing works
Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells.
Zegarra-Moro, O. L., Schmidt, L. J., Huang, H., & Tindall, D. J. (2002) · PubMed · Cited by 395 · see citing works
Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process.
Craft, N. A., Chhor, C. M., Tran, C., Belldegrun, A. S., deKernion, J. B., Witte, O. N., SAID, J. W., Reiter, R. E., & Sawyers, C. L. (1999) · PubMed · Cited by 291 · see citing works
Androgen receptor as a target in androgen-independent prostate cancer
Balk, S. P. (2002) · Urology · doi:10.1016/s0090-4295(02)01593-5 · Cited by 264 · see citing works
Progression of LNCaP Prostate Tumor Cells during Androgen Deprivation: Hormone-Independent Growth, Repression of Proliferation by Androgen, and Role for p27Kip1 in Androgen-Induced Cell Cycle Arrest
Kokontis, J. M., Hay, N., & Liao, S. (1998) · Molecular Endocrinology · doi:10.1210/mend.12.7.0136 · Cited by 250 · see citing works
Glial Fibrillary Acidic Protein: Regulation by Hormones, Cytokines, and Growth Factors
Laping, N. J., Teter, B., Nichols, N. R., Rozovsky, I., & Finch, C. E. (1994) · Brain Pathology · doi:10.1111/j.1750-3639.1994.tb00841.x · Cited by 233 · see citing works
The role of androgens and the androgen receptor in prostate cancer.
Debes, J. D., & Tindall, D. J. (2002) · Cancer Letters · doi:10.1016/s0304-3835(02)00413-5 · Cited by 191 · see citing works
Androgens Stimulate Lipogenic Gene Expression in Prostate Cancer Cells by Activation of the Sterol Regulatory Element-Binding Protein Cleavage Activating Protein/Sterol Regulatory Element-Binding Protein Pathway
Heemers, H. V., Maes, B., Foufelle, F., Heyns, W., Verhoeven, G., & Swinnen, J. V. (2001) · Molecular Endocrinology · doi:10.1210/mend.15.10.0703 · Cited by 172 · see citing works
TRANSDIFFERENTIATION OF PROSTATE CANCER CELLS TO A NEUROENDOCRINE CELL PHENOTYPE IN VITRO AND IN VIVO
Burchardt, T., Burchardt, M., Chen, M., Cao, Y., TAILLE, A. D. L., SHABSIGH, A., Hayek, O., Dorai, T., & Buttyan, R. E. (1999) · The Journal of Urology · doi:10.1016/s0022-5347(05)68241-9 · Cited by 169 · see citing works
Androgen Regulation of Programmed Death of Normal and Malignant Prostatic Cells
Isaacs, J. T., Lundmo, P. I., Berges, R. R., et al. (1992) · Journal of Andrology · doi:10.1002/j.1939-4640.1992.tb00337.x · Cited by 168 · see citing works
Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides
Eder, I. E., Čulig, Z., Ramoner, R. E., Thurnher, M., Putz, T., Nessler‐Menardi, C., Tiefenthaler, M., Bartsch, G. H., & Klocker, H. (2000) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7700202 · Cited by 152 · see citing works
Molecular Mechanisms of Androgen Action
Lindzey, J. K., Kumar, M. V., Grossman, M., Young, C. Y. F., & Tindall, D. J. (1994) · Vitamins and hormones · doi:10.1016/s0083-6729(08)61151-6 · Cited by 146 · see citing works
The use of cell lines in neurobiology
Lendahl, U., & McKay, R. D. G. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90004-t · Cited by 128 · see citing works
Molecular genetics of prostate cancer
Elo, J. P., & Visakorpi, T. (2001) · Annals of Medicine · doi:10.3109/07853890109002068 · Cited by 125 · see citing works
Androgen receptor expression in androgen‐independent prostate cancer cell lines
Chlenski, A., Nakashiro, K., Ketels, K. V., et al. (2001) · The Prostate · doi:10.1002/pros.1048 · Cited by 124 · see citing works
Molecular Biology of the Androgen Receptor: From Molecular Understanding to the Clinic
Eder, I. E., Čulig, Z., Putz, T., Nessler‐Menardi, C., Bartsch, G. H., & Klocker, H. (2001) · European Urology · doi:10.1159/000049782 · Cited by 122 · see citing works
Radical Prostatectomy for the Treatment of Localized Prostatic Carcinoma
Walsh, P. C. (1980) · Urologic Clinics of North America · doi:10.1016/s0094-0143(21)00146-4 · Cited by 114 · see citing works
Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference
Caplen, N. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.2.175 · Cited by 112 · see citing works
Tumor angiogenesis is associated with progression after radical prostatectomy in pT2/pT3 prostate cancer
Strohmeyer, D., R�ssing, C., Strauss, F., Bauerfeind, A., Kaufmann, O., & Loening, S. A. (2000) · The Prostate · doi:10.1002/(sici)1097-0045(20000101)42:1 · Cited by 110 · see citing works
Radical Prostatectomy for the Treatment of Localized Prostatic Cancer
Walsh, P. C., Oesterling, J. E., & Lepor, H. (1988) · Springer eBooks · doi:10.1007/978-1-4613-1667-1_11 · Cited by 105 · see citing works
Transition to androgen-independence in prostate cancer
Navarro, D., Luzardo, O. P., Fernández‐Pérez, L., et al. (2002) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(02)00064-x · Cited by 94 · see citing works
Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype
Zelivianski, S., Verni, M., Moore, C. R., et al. (2001) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(01)00087-8 · Cited by 90 · see citing works
Molecular Mechanisms of Androgen-Independent Growth of Human Prostate Cancer LNCaP-AI Cells1
Lu, S., Tsai, S. Y., & Tsai, M. (1999) · Endocrinology · doi:10.1210/endo.140.11.7086 · Cited by 86 · see citing works
Self-citation
The human prostatic cancer cell line LNCaP and its derived sublines: An in vitro model for the study of androgen sensitivity
van Steenbrugge, G. J., van Uffelen, C. J. C., Bolt, J., et al. (1991) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(91)90184-7 · Cited by 84 · see citing works
Pathophysiologic interactions in skeletal metastasis
Orr, F. W., Lee, J., Duivenvoorden, W., & Singh, G. (2000) · Cancer · doi:10.1002/1097-0142(20000615)88:12+ · Cited by 79 · see citing works
Prolactin and testosterone regulation of mitochondrial zinc in prostate epithelial cells
Liu, Y., FRANKLIN, R. B., & Costello, L. C. (1997) · The Prostate · doi:10.1002/(sici)1097-0045(19970101)30:1 · Cited by 69 · see citing works
Fas ligand is constitutively secreted by prostate cancer cells in vitro.
Liu, Q. Y., Rubin, M. A., Omene, C., et al. (1998) · PubMed · Cited by 68 · see citing works
Cytotoxic sensitivity to tumor necrosis factor-? in PC3 and LNCaP prostatic cancer cells is regulated by extracellular levels of SGP-2 (clusterin)
Sintich, S. M., Steinberg, J., Kozlowski, J. M., Lee, C., Pruden, S. J., Sayeed, S., & Sensibar, J. A. (1999) · The Prostate · doi:10.1002/(sici)1097-0045(19990501)39:2 · Cited by 66 · see citing works
Molecular Biology of the Androgen Receptor
Prins, G. S. (2000) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(19)30639-1 · Cited by 49 · see citing works
Partial characterization of a thyroid‐stimulating hormone‐like peptide in neuroendocrine cells of the human prostate gland
Abrahamsson, P., & Lilja, H. G. (1989) · The Prostate · doi:10.1002/pros.2990140109 · Cited by 48 · see citing works
Testosterone and estrogen affect neuronal differentiation but not proliferation in early embryonic cortex of the rat: the possible roles of androgen and estrogen receptors
Zhang, L., Zhang, L., Chang, Y. H., et al. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00942-8 · Cited by 44 · see citing works
Neuroendocrine Cells in Benign Prostatic Hyperplasia and Prostatic Carcinoma: Effect of Hormonal Treatment
Guate, J. L., Escaf, S., Menéndez, C. L., et al. (2010) · Urologia Internationalis · doi:10.1159/000283051 · Cited by 32 · see citing works
Molecular Mechanisms of Androgen-Independent Growth of Human Prostate Cancer LNCaP-AI Cells
Lu, S. J. (1999) · Endocrinology · doi:10.1210/en.140.11.5054 · Cited by 32 · see citing works
Target Antigens for Prostate Cancer Immunotherapy
Saffran, D. C., Reiter, R. E., Jakobovits, A., et al. (1999) · Cancer and Metastasis Reviews · doi:10.1023/a:1006333222424 · Cited by 28 · see citing works
Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation : specificity for steroids and antihormones
Wilson, E. M., Kemppainen, J. A., Sar, M., et al. (2021) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/gm96-j239 · Cited by 23 · see citing works
TRANSDIFFERENTIATION OF PROSTATE CANCER CELLS TO A NEUROENDOCRINE CELL PHENOTYPE IN VITRO AND IN VIVO
Burchardt, T., Burchardt, M., CHEN, M.-W., et al. (1999) · The Journal of Urology · doi:10.1097/00005392-199911000-00073 · Cited by 17 · see citing works
Androgen receptor expression in androgen‐independent prostate cancer cell lines
Chlenski, A., Nakashiro, K., Ketels, K. V., et al. (2001) · The Prostate · doi:10.1002/pros.1048.abs · Cited by 8 · see citing works
Characterization of developmental stage and neuronal potential of the rat PNS-derived stem cell line, RT4-AC
Donahue, L. M., Coates, P. W., & Reinhart, A. J. (1996) · Developmental Brain Research · doi:10.1016/0165-3806(96)00028-4 · Cited by 5 · see citing works

Flagged first, then by citations

Sorted by citations

An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression
Yu, J., Yu, J., Mani, R.-S., Cao, Q., Brenner, C. J., Cao, X., Wang, X., Wu, L., Li, J., Hu, M., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.018 · Cited by 850 · see citing works
Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer
Lamont, K. R., & Tindall, D. J. (2011) · Molecular Endocrinology · doi:10.1210/me.2010-0469 · Cited by 150 · see citing works

Id-1 expression in androgen-dependent prostate cancer is negatively regulated by androgen through androgen receptor
Xu, B., Sun, Y., Tang, G., Xu, C., Wang, L., Zhang, Y., & Ji, J. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.01.007 · Cited by 12 · see citing works
A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells
Li, T.-H., Zhao, H., Peng, Y., Beliakoff, J., Brooks, J. D., & Sun, Z. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm198 · Cited by 53 · see citing works
Androgens and the Thymus*
Pearce, P., Khalid, B. A. K., & Funder, J. W. (1981) · Endocrinology · doi:10.1210/endo-109-4-1073 · Cited by 74 · see citing works
Role of Androgen Receptor in Growth of Androgen Independent Prostate Cancer
Chen, C. D. (2003) · doi:10.21236/ada417515
Prostate Cancer Cells Increase Androgen Sensitivity by Increase in Nuclear Androgen Receptor and Androgen Receptor Coactivators; A Possible Mechanism of Hormone-Resistance of Prostate Cancer Cells
Fujimoto, N., Miyamoto, H., Mizokami, A., Harada, S., Nomura, M. J., Ueta, Y., Sasaguri, T., & Matsumoto, T. (2007) · Cancer Investigation · doi:10.1080/07357900601130698 · Cited by 49 · see citing works

Authors: Wright, M. E., Tsai, M.-J., & Aebersold, R.
Affiliations: Institute for Systems Biology (US)
Baylor College of Medicine (US)
Corresponding author: Wright, Michael E.
ORCID: Wright, Michael E.
Tsai, Ming-Jer
Aebersold, Ruedi
Venue: Molecular Endocrinology
Publisher: The Endocrine Society
Published: 2003-09
Volume: 17
Issue: 9
Pages: 1726-1737
ISSN: 0888-8809 (ISSN-L)
1944-9917
DOI: 10.1210/me.2003-0031
OpenAlex: W2156162122
Cited by: 166
References: 51
Citations by year: 2026: 2 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 2 · 2019: 4 · 2018: 11 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 9 · 2013: 9 · 2012: 4
FWCI: 7.87
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Molecular Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (CA58204)
National Cancer Institute (1R33CA93302, CA-58204, P50CA058204, R33CA093302)
National Institute of Diabetes and Digestive and Kidney Diseases (DK 62821, R01DK062821)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords: androgen receptor, neuroendocrine transdifferentiation, prostate cancer, castration-resistant prostate cancer, androgen withdrawal, androgen deprivation therapy, neuron-specific enolase, TUBB3, glial fibrillary acidic protein, nestin, LNCaP cells, cell proliferation, dendritic processes
MeSH terms: Carcinoma, Cell Differentiation, Humans, Male, Neurosecretory Systems, Phenotype, Prostatic Neoplasms, Receptors, Androgen, Tumor Cells, Cultured, Biomarkers, Gene Silencing, RNA Interference, RNA, Small Interfering

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells.

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks