Downregulation of Androgen Receptor Transcription by Promoter G-Quadruplex Stabilization as a Potential Alternative Treatment for Castrate-Resistant Prostate Cancer

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• 作者：Tom Mitchell ; Antonio Ramos-Montoya ; Marco Di Antonio ; Pierre Murat ; Stephan Ohnmacht ; Marialuisa Micco ; Sarah Jurmeister ; Lee Fryer ; Shankar Balasubramanian ; Stephen Neidle ; David E. Neal
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：February 26, 2013
• 年：2013
• 卷：52
• 期：8
• 页码：1429-1436
• 全文大小：322K
• 年卷期：v.52,no.8(February 26, 2013)
• ISSN：1520-4995

文摘

Androgen receptor (AR) signaling remains an important regulatory pathway in castrate-resistant prostate cancer, and its transcriptional downregulation could provide a new line of therapy. A number of small-molecule ligands have previously demonstrated the ability to stabilize G-quadruplex structures and affect gene transcription for those genes whose promoters contain a quadruplex-forming sequence. Herein, we report the probable formation of new G-quadruplex structure present in the AR promoter in a transcriptionally important location. NMR spectroscopy, circular dichroism, UV spectroscopy, and UV thermal melting experiments for this sequence are consistent with G-quadruplex formation. Fluorescence resonance energy transfer (FRET) melting studies have identified a novel compound, MM45, which appears to stabilize this G-quadruplex at submicromolar concentrations. The effects of MM45 have been investigated in prostate cancer cell lines where it has been shown to inhibit cell growth. A reporter assay intended to isolate the effect of MM45 on the G-quadruplex sequence showed dose-dependent transcriptional repression only when the AR promoter G-quadruplex sequence is present. Dose-dependent transcriptional repression of the AR by MM45 has been demonstrated at both a protein and mRNA level. This proof of concept study paves the route toward a potential alternative treatment pathway in castrate-resistant prostate cancer.