Androgen and the blocking of radiation-induced sensitization to Fas-mediated apoptosis through c-jun induction in prostate cancer cells.
OBJECTIVE
To clarify the key mechanism by which androgen makes prostate cancer cells highly resistant to Fas-mediated apoptosis.


METHODS
The role of c-jun induction by 10 nM dihydrotestosterone (DHT) in 5 Gy radiation-induced up-regulation of Fas and sensitization to the apoptosis was studied by using the human prostate cancer cell line LNCaP.


RESULTS
On exposure to 5 Gy radiation, LNCaP cells demonstrated high sensitization to Fas-mediated apoptosis through increased Fas expression, stabilized p53 expression and binding to p53 response elements within the promoter and first intronic region of the Fas gene. Following treatment with DHT, in vivo binding of p53 to its response elements was strongly inhibited. In addition, DHT significantly up-regulated c-jun expression through extracellular stress-regulated kinase (ERK) activation, and transfection of an antisense oligonucleotide for c-jun or ERK inhibition by PD98059 cancelled DHT-mediated suppression of radiation-induced transactivation of Fas gene and sensitization to Fas-mediated apoptosis.


CONCLUSIONS
Radiation-induced Fas sensitization in prostate cancer cell was mediated through p53-dependent transactivation of the Fas gene, which can be blocked by androgen stimulation mainly through induction of c-jun.
Shimada
K
K
Department of Pathology Nara Medical University 840 Shijo-cho Kashihara Nara 634-8521, Japan.
Nakamura
M
M
Ishida
E
E
Kishi
M
M
Konishi
N
N
D000728:Androgens / Q000378:metabolism*; D017209:Apoptosis; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D003360:Cosmids; D053938:DNA Fragmentation; D013196:Dihydrotestosterone / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000473:pathology*; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D000728:Androgens; D002843:Chromatin; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016376:Oligonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D013196:Dihydrotestosterone; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one