title: Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer.
abstract: 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.
authors.affiliation: Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Arima
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kubo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kagara
authors.forename: Ryouichirou
authors.initials: R
authors.lastname: Matsuda
authors.forename: Kazuki
authors.initials: K
authors.lastname: Toki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tatarano
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Idesako
authors.forename: Kenryu
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakagawa
mesh_terms: 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
chemical_list: 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