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Updated: Dec 18, 2025
Isolation of Cancer Stem Cells From Human Prostate Cancer Samples
Published on: March 14, 2014
Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells
Belén G Sánchez1, Alicia Bort1, Diana Vara-Ciruelos1
1Department of System Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
Abstract:
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.
Insights
Prostate cancer cells adapt to androgen deprivation by becoming neuroendocrine and stem-like, developing resistance to therapies. Restoring AMP-activated kinase (AMPK) reverses this plasticity and re-sensitizes cells to treatment.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Cell plasticity enables prostate cancer to evade targeted therapies by switching to neuroendocrine phenotypes.
- Neuroendocrine prostate cancer is linked to treatment failure and poor prognosis.
Purpose of the Study:
- To investigate the role of androgen signaling in driving prostate cancer cell plasticity towards a neuroendocrine and stem-like state.
- To elucidate the underlying molecular mechanisms, including the involvement of AMP-activated kinase (AMPK) and hypoxia-inducible factor 1-alpha (HIF-1α).
- To explore therapeutic strategies for overcoming treatment resistance associated with this plasticity.
Main Methods:
- Prostate cancer LNCaP cells were cultured under long-term androgen-depleted conditions.
- Neuroendocrine and stem cell markers were analyzed using morphological and molecular techniques.
- Cell viability assays were performed to assess resistance to docetaxel and 2-hydroxyflutamide.
- AMPK and HIF-1α pathways were manipulated via overexpression and assessed for their impact on cell phenotype and drug sensitivity.
Main Results:
- Androgen depletion induced a neuroendocrine phenotype in LNCaP cells, characterized by increased expression of βIII-tubulin and neuron-specific enolase (NSE).
- Prolonged androgen deprivation led to the development of stem-like cells with enhanced expression of CD133, ALDH1A1, ABCB1A, Nanog, Oct4, and VEGF, alongside inhibited E-cadherin.
- These stem-like cells exhibited resistance to docetaxel and 2-hydroxyflutamide, associated with decreased AMPK activation and increased HIF-1α stabilization.
- Overexpression of AMPK in stem-like cells reduced stemness markers, HIF-1α, and VEGF, restored E-cadherin and PGC-1α, and re-sensitized cells to docetaxel.
Conclusions:
- Long-term androgen deprivation drives prostate cancer cell plasticity towards a neuroendocrine and stem-like state, conferring therapeutic resistance.
- A novel regulatory mechanism involving the interplay between AMPK, HIF-1α, and E-cadherin in prostate cancer plasticity has been identified.
- Restoring AMPK activity represents a potential therapeutic strategy to overcome treatment resistance in advanced prostate cancer.
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