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Androgen receptor?mediated upregulation of quaking affects androgen receptor?related prostate cancer development and anti?androgen receptor therapy.

ABSTRACT: The androgen receptor (AR) has a crucial role in prostate cancer. RNA?binding protein?mediated post?transcriptional regulation is important in the initiation and development of cancer. The present study attempted to elucidate the mutual association of AR and RNA?binding protein quaking (QKI) in the development of prostate cancer. Dual?luciferase reporter demonstrated that AR can positively regulate the expression of QKI in prostate cancer cell lines due to its effective transcription regulating function. In addition, QKI may increase expression of AR by heat shock protein 90, which is a coactivator of AR, and silencing QKI can increase the sensitive of Casodex, which is an antagonist of AR in castration?resistant prostate cancer. This may be a new strategy for advanced prostate cancer.

SUBMITTER: Zhang K

PROVIDER: S-EPMC5984001 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Androgen receptor‑mediated upregulation of quaking affects androgen receptor‑related prostate cancer development and anti‑androgen receptor therapy.

Zhang Keke K Yan Fei F Lei Xiaoying X Wei Di D Lu Huanyu H Zhu Zheng Z Xiang An A Ye Zichen Z Wang Li L Zheng Wanxiang W Li Xi'an X Yuan Jiarui J Lu Zifan Z Yuan Jianlin J

Molecular medicine reports 20180413 6

The androgen receptor (AR) has a crucial role in prostate cancer. RNA‑binding protein‑mediated post‑transcriptional regulation is important in the initiation and development of cancer. The present study attempted to elucidate the mutual association of AR and RNA‑binding protein quaking (QKI) in the development of prostate cancer. Dual‑luciferase reporter demonstrated that AR can positively regulate the expression of QKI in prostate cancer cell lines due to its effective transcription regulating ...[more]

PMID: 29658587

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Project description:Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies.

Dataset Information

Androgen receptor?mediated upregulation of quaking affects androgen receptor?related prostate cancer development and anti?androgen receptor therapy.

Publications

Androgen receptor‑mediated upregulation of quaking affects androgen receptor‑related prostate cancer development and anti‑androgen receptor therapy.

Similar Datasets

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