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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.

Original publication

DOI

10.1021/bi301349c

Type

Journal article

Journal

Biochemistry

Publication Date

26/02/2013

Volume

52

Pages

1429 - 1436

Keywords

Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Circular Dichroism, Down-Regulation, Fluorescence Resonance Energy Transfer, G-Quadruplexes, Gene Expression Regulation, Neoplastic, Humans, Imides, Male, Naphthalenes, Nuclear Magnetic Resonance, Biomolecular, Promoter Regions, Genetic, Prostate, Prostatic Neoplasms, Receptors, Androgen, Spectrophotometry, Ultraviolet, Transcriptional Activation