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Open AccessArticle

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

1
Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain
2
Chemical Research Institute “Andrés M. del Río” (IQAR), Alcalá University, 28871 Alcalá de Henares, Madrid, Spain
*
Author to whom correspondence should be addressed.
Cells 2020, 9(6), 1441; https://doi.org/10.3390/cells9061441
Received: 21 April 2020 / Revised: 4 June 2020 / Accepted: 8 June 2020 / Published: 10 June 2020
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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.
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Keywords: AMPK; neuroendocrine cells; cancer stem cells; lineage plasticity; prostate cancer AMPK; neuroendocrine cells; cancer stem cells; lineage plasticity; prostate cancer
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MDPI and ACS Style

Sánchez, B.G.; Bort, A.; Vara-Ciruelos, D.; Díaz-Laviada, I. Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells. Cells 2020, 9, 1441.

AMA Style

Sánchez BG, Bort A, Vara-Ciruelos D, Díaz-Laviada I. Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells. Cells. 2020; 9(6):1441.

Chicago/Turabian Style

Sánchez, Belén G.; Bort, Alicia; Vara-Ciruelos, Diana; Díaz-Laviada, Inés. 2020. "Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells" Cells 9, no. 6: 1441.

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