Nuclear translocation of ADAM‐10 contributes to the pathogenesis and progression of human prostate cancer

Abstract

A disintegrin and metalloproteases (ADAM) are cell membraneanchored 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 5α α α α-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 androgendependent PC cells. Immunocytochemistry revealed that after 5α α α α-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 Tfactor (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. (Cancer Sci 2007; 98: 1720-1726) A disintegrin and metalloproteases (ADAM) are members of the metzincin (zinc-dependent metalloprotease) superfamily. They are cell membrane-anchored cell surface proteins involved in the proteolytic processing of other transmembrane proteins, in cell adhesion and in cell signaling events.(1-3) Among the more than 30 characterized ADAM proteins, ADAM-9, -10 and -17 act as cell surface 'sheddases', cleaving the extracellular (ecto) domains of cell membrane-bound proteins, including amyloid precursor proteins that have been investigated in Alzheimer's disease.(4) These ADAM are highly expressed in human breast, lung, stomach, colon, pancreas, uterine, ovarian and prostate cancer.(5-11) They activate growth factors such as epidermal growth factor and transforming growth factor-α, cytokines such as tumor necrosis factor-α, and degrade cell adhesion molecules such as CD44, L1 and collagens, all of which are synthesized as precursors and are responsible for cancer development. (12,13) Prostate cancer (PC) is one of the most common malignancies among men. Global cancer statistics indicated that in 2002, 5.8% of cancer deaths in men and 3.3% of all cancer deaths were attributable to PC. (14) In the development of PC, 5α-dihyd...

ADAM10, the Rate-limiting Protease of Regulated Intramembrane Proteolysis of Notch and Other Proteins, Is Processed by ADAMS-9, ADAMS-15, and the γ-Secretase

“…Both Cajal bodies and PML bodies are associated with actively transcribed gene loci involved in cell survival control (61,62), providing further circumstantial evidence for a nuclear function of ADAM10. Recently, translocation and colocalization of an ϳ60-kDa enzymatically active form of ADAM10 with the androgen receptor in the nuclear fraction of a prostate cancer was observed (68), opening the debate as to how these observations are interrelated with our observations of the 4-kDa ADAM10 nuclear fragment.…”

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

“…Ko et al (17) demonstrated that the expression of ADAM10 was correlated with increased growth of oral squamous cell carcinoma cells. Arima et al (27) confirmed that suppression of ADAM10 expression leads to a significant decrease in prostate cancer cell growth. The effect of ADAM10 on tumor cell growth may be related to its protease activity.…”

Inhibition of Amyloid Precursor Protein Processing Enhances Gemcitabine-mediated Cytotoxicity in Pancreatic Cancer Cells

“…2A, panels 2 and 3). Based on published reports (29,30), the proenzyme form of ADAM10 migrates at ϳ100 kDa on a SDS-PAGE gel and the metabolically active form at ϳ60 kDa. Treatment with batimastat showed an increase in the levels of an ϳ80 kDa form of ADAM10, which was associated with a decrease in sAPP␣ generation (Fig.…”