Phosphorylation status of Fas-associated death domain-containing protein regulates telomerase activity and strongly correlates with prostate cancer outcomes.
OBJECTIVE
We investigated whether the phosphorylated Fas-associated death domain protein (FADD) at serine 194 regulated human telomerase reverse transcriptase (hTERT) expression, telomerase activity and cancer progression using prostate cancer cell lines and radical prostatectomy samples taken from patients receiving neoadjuvant hormonal therapy (NHT).


METHODS
We analyzed hTERT expression, telomerase activity and invasion capacity in prostate cancer cell lines overexpressing the wild-type or mutant form of FADD (S194D or A). FADD, phosphorylated FADD (p-FADD) and hTERT expression in viable prostate cancer cells following NHT were immunohistochemically examined using 50 prostatectomy samples.


RESULTS
Dephosphorylated FADD (S194A) overexpression enhanced hTERT expression and telomerase activity, resulting in increased cell proliferation and invasion capacity. In Kaplan-Meier survival analysis, the patients with prostate cancer expressing low levels of p-FADD and high levels of hTERT had significantly higher rates of biochemical recurrence than those with high p-FADD and low hTERT expression (p < 0.001).


CONCLUSIONS
The phosphorylation status of FADD at serine 194 could strongly affect survival and invasion of prostate cancer cells via modulation of hTERT expression and telomerase activity. p-FADD and hTERT expression may have potential as new biomarkers predicting the biochemical recurrence after NHT.
Matsumura
Yoshiaki
Y
Department of Urology, Nara Medical University, Nara 634-8522, Japan. ymatsumu@tcc.pref.tochigi.jp
Shimada
Keiji
K
Tanaka
Nobumichi
N
Fujimoto
Kiyohide
K
Hirao
Yoshihiko
Y
Konishi
Noboru
N
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D018450:Disease Progression; D004359:Drug Therapy, Combination; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019098:Telomerase / Q000378:metabolism*
D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D053200:Fas-Associated Death Domain Protein; C509186:TERT protein, human; D019098:Telomerase