New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells

Soo Ok Lee, Zhifang Ma, Chiuan Ren Yeh, Jie Luo, Tzu Hua Lin, Kuo Pao Lai, Shinichi Yamashita, Liang Liang, Jing Tian, Lei Li, Qi Jiang, Chiung Kuei Huang, Yuanjie Niu, Shuyuan Yeh, Chawnshang Chang

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14-26
Number of pages13
JournalJournal of Molecular Cell Biology
Volume5
Issue number1
DOIs
Publication statusPublished - 2013 Feb
Externally publishedYes

Keywords

  • androgen receptor
  • combination therapy
  • prostate cancer stem cells

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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