Expression of the Disintegrin Metalloprotease, ADAM-10, in Prostate Cancer and Its Regulation by Dihydrotestosterone, Insulin-Like Growth Factor I, and Epidermal Growth Factor in the Prostate Cancer Cell Model LNCaP

Abstract

Purpose:The disintegrin metalloprotease ADAM-10 is a multidomain metalloprotease that is potentially significant in tumor progression due to its extracellular matrix-degrading properties. Previously, ADAM-10 mRNA was detected in prostate cancer (PCa) cell lines; however, the presence of ADAM-10 protein and its cellular localization, regulation, and role have yet to be described. We hypothesized that ADAM-10 mRNA and protein may be regulated by growth factors such as 5␣-dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor, known modulators of PCa cell growth and invasion.Experimental Design: ADAM-10 expression was analyzed by in situ hybridization and immunohistochemistry in prostate tissues obtained from 23 patients with prostate disease. ADAM-10 regulation was assessed using quantitative reverse transcription-PCR and Western blot analysis in the PCa cell line LNCaP.Results: ADAM-10 expression was localized to the secretory cells of prostate glands, with additional basal cell expression in benign glands. ADAM-10 protein was predominantly membrane bound in benign glands but showed marked nuclear localization in cancer glands. By Western blot, the 100-kDa proform and the 60-kDa active form of ADAM-10 were synergistically up-regulated in LNCaP cells treated with insulin-like growth factor I plus 5␣-dihydrotestosterone. Epidermal growth factor also up-regulated both ADAM-10 mRNA and protein.Conclusions: This study describes for the first time the expression, regulation, and cellular localization of ADAM-10 protein in PCa. The regulation and membrane localization of ADAM-10 support our hypothesis that ADAM-10 has a role in extracellular matrix maintenance and cell invasion, although the potential role of nuclear ADAM-10 is not yet known.

Expression of a-disintegrin and metalloproteinase 10 correlates with grade of malignancy in human glioma

“…The results of the present study demonstrated that the higher the tumor grade, the higher the ADAM10 expression level, and thus the more aggressive the tumor. In accordance with existing evidence (12)(13)(14)(15)(16)(17)(18)(19)(20)28,31,33,34), one hypothesis is that ADAM10 promotes the invasive growth of glioma cells by hydrolyzing extracellular matrix collagen. This hydrolysis may transmit intercellular signals and promote subsequent ectodomain EGFR ligand shedding, thus stimulating intracellular relevant genes to increase tumor cell proliferation.…”

“…Previous studies have reported that a number of ADAMs are involved in the biological processes of malignant tumor cells, including proliferation and invasive growth (26)(27)(28)(29)(30). In addition, ADAM10 has been found to be highly expressed in local secretory cells in prostate cancer and expressed in the basal cells of benign glands, while aberrant ADAM10 expression has been demonstrated to correlate with osteosarcoma progression (17,31,32). A previous study has demonstrated that ADAM10 promotes the proliferation of gastric cancer cells by mediating ectodomain shedding and, therefore, activating epidermal growth factor receptor ligands (25).…”

Aberrant Expression of a Disintegrin and Metalloproteinase 17/Tumor Necrosis Factor-α Converting Enzyme Increases the Malignant Potential in Human Pancreatic Ductal Adenocarcinoma

“…Although ADAM17/TACE is the most important molecule in the release of TNF-a, our results cannot exclude the possibility that other molecules might be involved in TNF-a shedding. Pancreatic cancer cells also express ADAM10 (data not shown), 6 which is considered to be an additional candidate for a TNF-a processing enzyme (30). However, the physiologic TNF-a shedding activity of ADAM10 is not clear yet.…”

“…ADAM molecules have the unique potential to combine various physiologic functions, including cell fusion, cell adhesion, intracellular signaling, and proteolytic processing of molecules (3)(4)(5). In addition, ADAM molecules play a critical role in malignant neoplasms (6,7). A small subset of the presently known ADAM molecules show catalytic activity (8).…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…ADAM-10 is specifically expressed on the cell surface of normal epithelial cells [133] while tumour cells show mainly nuclear staining for ADAM-10 suggesting an interaction with nuclear proteins or DNA [134].…”