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...
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MDPI AG
2020-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/6/1441 |
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| author | Belén G. Sánchez Alicia Bort Diana Vara-Ciruelos Inés Díaz-Laviada |
| author_facet | Belén G. Sánchez Alicia Bort Diana Vara-Ciruelos Inés Díaz-Laviada |
| author_sort | Belén G. Sánchez |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T19:15:53Z |
| format | Article |
| id | doaj.art-45a39ee69f474140a9a5567f1ee3b3ab |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:15:53Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-45a39ee69f474140a9a5567f1ee3b3ab2023-11-20T03:24:35ZengMDPI AGCells2073-44092020-06-0196144110.3390/cells9061441Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like CellsBelén G. Sánchez0Alicia Bort1Diana Vara-Ciruelos2Inés Díaz-Laviada3Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, SpainDepartment of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, SpainDepartment of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, SpainDepartment of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, SpainIn 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.https://www.mdpi.com/2073-4409/9/6/1441AMPKneuroendocrine cellscancer stem cellslineage plasticityprostate cancer |
| spellingShingle | Belén G. Sánchez Alicia Bort Diana Vara-Ciruelos Inés Díaz-Laviada Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells Cells AMPK neuroendocrine cells cancer stem cells lineage plasticity prostate cancer |
| 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 | AMPK neuroendocrine cells cancer stem cells lineage plasticity prostate cancer |
| url | https://www.mdpi.com/2073-4409/9/6/1441 |
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