Interaction between the androgen receptor and RNase L mediates a cross-talk between the interferon and androgen signaling pathways.
Signaling by androgens and interferons (IFN) plays an important role in prostate cancer initiation and progression. Using microarray analysis, we describe here a functional cross-talk between dihydrotestosterone and interferon signaling. Glutathione S-transferase pull-down and co-immunoprecipitation experiments reveal that the androgen receptor and the interferon-activated RNase L interact with each other in a ligand-dependent manner. Furthermore, overexpression of wild type RNase L confers IFN sensitivity to a dihydrotestosterone-inducible reporter gene, whereas R462Q-mutated RNase L does not. Based on our data we hypothesize that in 22RV1 cells, activated androgen receptor (AR) contributes to the insensitivity to IFN of the cell. Accordingly, we show that AR knockdown restores responsiveness to IFNgamma. Our findings support a model in which both the activation of AR and the down-regulation of IFN signaling can synergize to promote cell survival and suppress apoptosis. This model provides the molecular basis to understand how mutated RNase L can lead to early onset PCa and illustrates how inflammatory cytokines and nuclear hormone signaling contribute to tumor development.
Bettoun
David J
DJ
Department of Molecular Endocrinology, Merck Research Laboratory, West Point, Pennsylvania 19486, USA. david_bettoun@merck.com
Scafonas
Angela
A
Rutledge
Su Jane
SJ
Hodor
Paul
P
Chen
Oliver
O
Gambone
Carlo
C
Vogel
Robert
R
McElwee-Witmer
Sheila
S
Bai
Chang
C
Freedman
Leonard
L
Schmidt
Azriel
A
D000728:Androgens / Q000378:metabolism; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D013196:Dihydrotestosterone / Q000494:pharmacology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008954:Models, Biological; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020239:Receptor Cross-Talk; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000728:Androgens; D008024:Ligands; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D007371:Interferon-gamma; D007372:Interferons; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease