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Interaction between the androgen receptor and RNase L mediates a cross-talk between the interferon and androgen

David J Bettoun1, Angela Scafonas, Su Jane Rutledge

  • 1Department of Molecular Endocrinology, Merck Research Laboratory, West Point, Pennsylvania 19486, USA. david_bettoun@merck.com

The Journal of Biological Chemistry
|September 17, 2005
PubMed

Insights

Androgen receptor (AR) and interferon (IFN) signaling pathways interact in prostate cancer. Activated AR may block IFN response, promoting cancer cell survival and potentially leading to early-onset prostate cancer (PCa).

Area of Science:

  • Molecular Biology
  • Oncology
  • Endocrinology

Background:

  • Androgen and interferon signaling are crucial in prostate cancer (PCa) development.
  • Understanding the interplay between these pathways is key to novel therapeutic strategies.

Purpose of the Study:

  • To investigate the functional cross-talk between dihydrotestosterone (DHT) and interferon (IFN) signaling.
  • To elucidate the role of androgen receptor (AR) and RNase L interaction in PCa progression.

Main Methods:

  • Microarray analysis to identify signaling interactions.
  • Glutathione S-transferase pull-down and co-immunoprecipitation to confirm protein interactions.
  • Reporter gene assays and gene knockdown to assess functional consequences.

Main Results:

  • Demonstrated ligand-dependent interaction between the androgen receptor (AR) and interferon-activated RNase L.
  • Wild-type RNase L conferred IFN sensitivity, while a mutated form (R462Q) did not.
  • Activated AR in 22RV1 cells was linked to IFN insensitivity; AR knockdown restored IFNgamma responsiveness.

Conclusions:

  • A model is proposed where activated AR and suppressed IFN signaling synergize to promote cell survival and inhibit apoptosis in PCa.
  • This interaction provides a molecular basis for understanding how mutated RNase L contributes to early-onset PCa.
  • Highlights the contribution of inflammatory cytokines and nuclear hormone signaling in tumor development.

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