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Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells
In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349866/ https://www.ncbi.nlm.nih.gov/pubmed/32531951 http://dx.doi.org/10.3390/cells9061441 |
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author | Sánchez, Belén G. Bort, Alicia Vara-Ciruelos, Diana Díaz-Laviada, Inés |
author_facet | Sánchez, Belén G. Bort, Alicia Vara-Ciruelos, Diana Díaz-Laviada, Inés |
author_sort | Sánchez, Belén G. |
collection | PubMed |
description | In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring. |
format | Online Article Text |
id | pubmed-7349866 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73498662020-07-15 Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells Sánchez, Belén G. Bort, Alicia Vara-Ciruelos, Diana Díaz-Laviada, Inés Cells Article In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring. MDPI 2020-06-10 /pmc/articles/PMC7349866/ /pubmed/32531951 http://dx.doi.org/10.3390/cells9061441 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sánchez, Belén G. Bort, Alicia Vara-Ciruelos, Diana Díaz-Laviada, Inés Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells |
title | Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells |
title_full | Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells |
title_fullStr | Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells |
title_full_unstemmed | Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells |
title_short | Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells |
title_sort | androgen deprivation induces reprogramming of prostate cancer cells to stem-like cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349866/ https://www.ncbi.nlm.nih.gov/pubmed/32531951 http://dx.doi.org/10.3390/cells9061441 |
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