Cross-talk between androgen receptor and pregnane and xenobiotic receptor reveals existence of a novel modulatory action of anti-androgenic drugs.
The androgen receptor (AR) is a member of nuclear receptor superfamily (NRs) and plays a critical role in prostate cancer development and progression. Therefore, anti-androgens that repress AR activity remain a critical mainstay for prostate cancer therapy. However, molecular mechanisms by which anti-androgens exert their therapeutic effects are not clearly elucidated and hence are a major area of scientific pursuit. Here, we demonstrate that another member of NRs, pregnane and xenobiotic receptor (PXR), not only acts as a molecular sensor of anti-androgens but also influences the outcome of therapeutic regimen with anti-androgenic drugs via a novel AR-PXR cross-talk. Using 'gain- and loss-of-function' studies, we identified a distinct role of PXR as a potent repressor of AR-regulated transcription. Our study implicates PXR as a key determinant of anti-androgen action since down-regulation of PXR diminishes the potency of the anti-androgenic drugs and enhances transcriptional actions of androgens. In addition, our subcellular localization studies revealed that ligand-activated AR induces nuclear localization of PXR and the two receptors colocalize at discrete sites in nucleus and mitotic chromatin. Finally, we report a distinct antagonist-induced interaction between AR and PXR defining a hitherto unidentified mode of action of AR antagonist. In this perspective, the study may help in designing and development of novel AR antagonists offering improved avenues in prostate cancer therapy.
Kumar
Subodh
S
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
Jaiswal
Bharti
B
Kumar
Sanjay
S
Negi
Seema
S
Tyagi
Rakesh K
RK
D000726:Androgen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000728:Androgens / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002843:Chromatin; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D004364:Pharmaceutical Preparations; D011467:Prostate / Q000378:metabolism / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D020239:Receptor Cross-Talk / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000627:therapeutic use; D015262:Xenobiotics / Q000627:therapeutic use
C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D002843:Chromatin; D004364:Pharmaceutical Preparations; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics