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Updated: May 20, 2026
Isolation of Stem-like Cells from 3-Dimensional Spheroid Cultures
Published on: December 13, 2019
New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs.
Soo Ok Lee1, Zhifang Ma, Chiuan-Ren Yeh
1George Whipple Lab for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Abstract:
The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
Insights
Androgen deprivation therapy for prostate cancer (PCa) may fail by increasing PCa stem cells. Targeting both stem and non-stem PCa cells simultaneously offers a promising new therapeutic strategy.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Prostate Cancer Research
Background:
- Androgen deprivation therapy (ADT) is standard for prostate cancer (PCa) but often fails, leading to castration-resistant PCa.
- ADT may inadvertently increase prostate cancer stem/progenitor cells, contributing to therapeutic failure.
Purpose of the Study:
- To investigate the differential role of the androgen receptor (AR) in PCa stem/progenitor versus non-stem/progenitor cells.
- To explore novel therapeutic strategies targeting both PCa stem and non-stem cells for improved treatment efficacy.
Main Methods:
- Analysis of PCa patient samples treated with ADT.
- In vitro studies using PCa cell lines with anti-androgens, AR-siRNA, and functional AR.
- In vivo studies using three mouse models of PCa.
- Evaluation of targeted therapies including AR degradation enhancer ASC-J9, 5-azathioprine, and γ-tocotrienol.
Main Results:
- ADT was associated with an increased PCa stem/progenitor cell population.
- AR signaling differentially affects PCa stem/progenitor and non-stem/progenitor cells.
- Combined targeting of stem/progenitor cells (5-azathioprine, γ-tocotrienol) and non-stem/progenitor cells (ASC-J9) significantly suppressed castration-resistant tumors.
Conclusions:
- Current ADT may promote PCa stem cell expansion, explaining treatment failure.
- Simultaneous targeting of both PCa stem/progenitor and non-stem/progenitor cells shows potential for a novel therapeutic approach.
- This combination therapy could be effective for both early-stage and castration-resistant prostate cancer.
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