The Role of the ADAM-15 Disintegrin in E-Cadherin Proteolysis and Prostate Cancer Metastasis
Annual rept. 20 Jan 2006-19 Jan 2007
MICHIGAN UNIV ANN ARBOR
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Proteolysis of E-cadherin was rigorously studied a decade ago with specific attention focused on metalloproteinase activity that cleaved E-cadherin in the extracellular domain and generated an 80kDa E-cad 80 fragment that was shown to disrupt epithelial cell-cell adhesion. This finding was of particular interest due to the fact that E-cad 80 was increased in the serum of cancer patients. Several of these studies demonstrated significant elevations in the serum of patients with gastric, hepatocellular, lung and breast cancer. Although several specific metalloproteinases were shown to cleave E-cadherin to the 80kDa species in vitro, these enzymes were not elevated in metastatic prostate cancer and were not tested under physiologic conditions. Through the use of cDNA microarray this laboratory identified a membrane bound, disentigrin metalloproteinase ADAM-15 that is specifically upregulated at both the transcriptional and translational level in metastatic prostate cancer. Based on these observations, we hypothesize that the truncation and inactivation of E-cadherin is mediated by the ADAM-15 disentigrin in metastatic prostate cancer. The primary goal of this proposal is to demonstrate that ADAM-15 truncates E-cadherin in prostate epithelial cells, and that this activity promotes the malignant transformation of these cells.
- Medicine and Medical Research