Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer.
A disintegrin and metalloproteases (ADAM) are cell membrane-anchored proteins with potential implications for the metastasis of human cancer cells via cell adhesion and protease activities. In prostate cancer (PC), the ADAM-10 protein showed a nuclear localization whereas in benign prostate hypertrophy (BPH) it was predominantly bound to the cell membrane. We hypothesized that the pathogenesis and progression of PC are attributable to the nuclear translocation of ADAM-10. Immunoblotting revealed that after 5alpha-dihydrotestosterone treatment, a 60-kDa active form of ADAM-10 was increased in the nuclear fraction but decreased in the cell membrane and cytoplasmic fractions of human androgen-dependent PC cells. Immunocytochemistry revealed that after 5alpha-dihydrotestosterone treatment, the ADAM-10 protein was translocated from the cell membrane to the nucleus. Coimmunoprecipitation of androgen receptor and ADAM-10 was detected in the nuclear fraction but not in the cell membrane and cytoplasmic fractions. Immunohistochemical study of 64 PC and 20 BPH samples showed that the intensity of ADAM-10 staining was significantly higher in the nuclei of PC cells than in the nuclei of BPH cells (P < 0.0001). It was also significantly lower in the cell membrane of PC cells than in the cell membrane of BPH cells (P = 0.0017). Nuclear staining intensity was significantly correlated with the clinical T-factor (P = 0.004), the Gleason score (P < 0.0001) and preoperative prostate-specific antigen levels (P = 0.0061). ADAM-10 small interfering RNA transfectants showed a significant decrease in cell growth compared to the controls. Our results suggest that in human PC, the nuclear translocation of ADAM-10 coupled with the androgen receptor is involved in tumor growth and progression.
Arima
Takashi
T
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
Enokida
Hideki
H
Kubo
Hiroyuki
H
Kagara
Ichiro
I
Matsuda
Ryouichirou
R
Toki
Kazuki
K
Nishimura
Hiroaki
H
Chiyomaru
Takeshi
T
Tatarano
Shuichi
S
Idesako
Toshihiko
T
Nishiyama
Kenryu
K
Nakagawa
Masayuki
M
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D013196:Dihydrotestosterone / Q000494:pharmacology; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D013196:Dihydrotestosterone; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human