8751

ADAM15

ADAM metallopeptidase domain 15;ADAM15;ADAM metallopeptidase domain 15

MDC-15|a disintegrin and metalloproteinase domain 15 (metargidin)|disintegrin and metalloproteinase domain-containing protein 15|metalloprotease RGD disintegrin protein|metalloproteinase-like, disintegrin-like, and cysteine-rich protein 15

1q21.3

protein-coding

The aim of the current study was to evaluate the expression of ADAM15 disintegrin (ADAM15) in a broad spectrum of human tumors. The transcript for ADAM15 was found to be highly upregulated in a variety of tumor cDNA expression arrays. ADAM15 protein expression was examined in tissue microarrays (TMAs) consisting of 638 tissue cores. TMA analysis revealed that ADAM15 protein was significantly increased in multiple types of adenocarcinoma, specifically in prostate and breast cancer specimens. Statistical association was observed with disease progression within clinical parameters of predictive outcome for both prostate and breast cancers, pertaining to Gleason sum and angioinvasion, respectively. In this report, we also present data from a cDNA microarray of prostate cancer (PCa), where we compared transfected LNCaP cells that overexpress ADAM15 to vector control cells. In these experiments, we found that ADAM15 expression was associated with the induction of specific proteases and protease inhibitors, particularly tissue inhibitor of metalloproteinase 2, as validated in a separate PCa TMA. These results suggest that ADAM15 is generally overexpressed in adenocarcinoma and is highly associated with metastatic progression of prostate and breast cancers.

ADAM15 (A Disintegrin And Metalloproteinase 15), a transmembrane protein containing seven domains, interacts with some integrins via its disintegrin domain and overexpresses in many solid tumors. In this study, the effect of the recombinant human disintegrin domain (rhddADAM15) on the proliferation and migration of Bel-7402 cells was evaluated in vitro and in vivo in zebrafish xenografts. rhddADAM15 (4 muM) severely inhibited the proliferation and migration of Bel-7402 cells, inducing a partial G2/S arrest and morphological nucleus changes of apoptosis. Moreover, the activity of caspases 8, 9 and 3 in Bel-7402 cells was increased. In addition, the zebrafish was used as a model for apoptosis-induction and tumor-xenograft. rhddADAM15 (1 pM) inhibited the growth and metastasis of Bel-7402 cell xenografts in zebrafish and a lower concentration (0.1 pM) induced severe apoptosis in the somatic cells of zebrafish. In conclusion, our data identified rhddADAM15 as a potent inhibitor of tumor growth and metastasis, making it a promising tool for use in anticancer treatment.

Proteins of the a disintegrin and metalloprotease (ADAM) family are transmembrane proteins involved in ectodomain shedding and in cellular interactions. In skin, ADAM-15 is detected in the epidermis and dermal vascular structures by immunolocalization. expression is also detected in isolated fibroblast, keratinocytes and endothelial cells in culture. Despite high expression of ADAM-15 throughout the wound repair process, wound healing experiments in vivo revealed a dispensable role of ADAM-15 for the healing process. No alterations in wound closure, re-epithelialization, contraction, scar formation and angiogenesis were detected in animals carrying ADAM-15-/- deletion. When analysing melanoma development by grafting melanoma cells into the flank of ADAM-15-/-, no significant alteration in tumor growth was detected. However, at later stages, melanomas in the ADAM-15-/- animals were smaller than those grown in WT animals. At all time points, no significant differences in vascularization of the peritumoral stroma and tumors were detected. Interestingly, we could detect a reduced number of metastasized lungs and lymph nodes in ADAM-15-/- animals as compared to control littermate mice. In conclusion, our study indicated that ADAM-15 is dispensable for cutaneous wound healing and B16F1 melanoma growth, but significantly contributes to metastasis formation.

Using human tumor and cDNA microarray technology, we have recently shown that the ADAM15 disintegrin is significantly overexpressed during the metastatic progression of human prostate cancer. In the current study, we used lentiviral-based short hairpin RNA (shRNA) technology to down-regulate ADAM15 in the metastatic prostate cancer cell line, PC-3. ADAM15 down-regulation dramatically attenuated many of the malignant characteristics of PC-3 cells in vitro and prevented the s.c. growth of PC-3 cells in severe combined immunodeficient (SCID) mice. By inhibiting the expression of ADAM15 in PC-3 cells, we showed decreased cell migration and adhesion to specific extracellular matrix proteins. This was accompanied by a reduction in the cleavage of N-cadherin by ADAM15 at the cell surface. Fluorescence-activated cell sorting analysis revealed reduced cell surface expression of the metastasis-associated proteins alpha(v) integrin and CD44. Furthermore, matrix metalloproteinase 9 secretion and activity were abrogated in response to ADAM15 reduction. In an in vitro model of vascular invasion, loss of ADAM15 reduced PC-3 adhesion to, and migration through, vascular endothelial cell monolayers. Using an SCID mouse model of human prostate cancer metastasis, we found that the loss of ADAM15 significantly attenuated the metastatic spread of PC-3 cells to bone. Taken together, these data strongly support a functional role for ADAM15 in prostate tumor cell interaction with vascular endothelium and the metastatic progression of human prostate cancer.