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Published on: September 8, 2017
Etoposide induces growth arrest and disrupts androgen receptor signaling in prostate cancer cells
Shicheng Liu1, Hitoshi Yamauchi
1Department of Research and Development, Nipro Patch Co., Ltd., Kasukabe, Saitama, Japan. liu@nipro-patch.co.jp
Abstract:
Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. The present study indicates that the topoisomerase II inhibitor etoposide strikingly inhibits androgen/AR-mediated cell growth and androgen-stimulated DNA synthesis in prostate cancer cells. Etoposide significantly repressed the AR mRNA and protein expression in a dose-dependent manner. Etoposide-mediated down-regulation of AR was associated with blocking androgen-induced AR translocation from cytoplasm into nucleus of cells. Additionally, etoposide disrupted the association of AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Etoposide simultaneously reduced the intracellular and secreted PSA levels, a marker for the progression of prostate cancer. These findings collectively reveal that etoposide not only serves as a traditional genotoxic agent but directly targets AR as an AR disrupting therapeutic strategy in prostate cancer.
Insights
Etoposide, a topoisomerase II inhibitor, effectively halts prostate cancer growth by targeting the androgen receptor (AR). This drug represses AR expression and function, offering a new therapeutic strategy for prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen receptor (AR) signaling is fundamental to prostate cancer development and progression.
- Targeting AR is a key strategy in treating prostate cancer.
Purpose of the Study:
- To investigate the effect of etoposide, a topoisomerase II inhibitor, on androgen/AR signaling in prostate cancer cells.
- To determine if etoposide can serve as an AR-disrupting agent for prostate cancer therapy.
Main Methods:
- Prostate cancer cells were treated with etoposide.
- AR mRNA and protein expression levels were measured.
- AR translocation, AR-HSP90 association, and androgen binding to AR were assessed.
- Intracellular and secreted prostate-specific antigen (PSA) levels were quantified.
Main Results:
- Etoposide significantly inhibited androgen/AR-mediated cell growth and DNA synthesis.
- Etoposide dose-dependently repressed AR mRNA and protein expression.
- Etoposide blocked androgen-induced AR nuclear translocation and disrupted AR-HSP90 association.
- Etoposide reduced PSA levels, indicating an effect on cancer progression.
Conclusions:
- Etoposide exhibits potent anti-prostate cancer activity by directly targeting the androgen receptor pathway.
- Etoposide acts as an AR-disrupting agent, suggesting its potential as a novel therapeutic strategy for prostate cancer.
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