ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer

• Published in: PloS one Vol. 11; no. 3; p. e0150138
• Main Authors: Lorenzatti Hiles, Guadalupe, Bucheit, Amanda, Rubin, John R., Hayward, Alexandra, Cates, Angelica L., Day, Kathleen C., El-Sawy, Layla, Kunju, L. Priya, Daignault, Stephanie, Lee, Cheryl T., Liebert, Monica, Hussain, Maha, Day, Mark L.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2016; Public Library of Science (PLoS)
• Subjects: Aberration; ADAM Proteins - genetics; ADAM Proteins - metabolism; Adhesion; Analysis; Biological activity; Biology and Life Sciences; Bladder; Bladder cancer; Breast cancer; Cancer; Cancer metastasis; Cancer therapies; Catalysis; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Databases, Genetic; Development and progression; Disease Progression; Endothelium; Epidermal growth factor; Gene expression; Genomes; Growth factors; Health aspects; Humans; Immunoreactivity; Invasiveness; Kinases; Medicine and Health Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neoplasm Staging; Prostate cancer; Quality; Research and Analysis Methods; Risk factors; Signaling; Staining; Switches; Tissues; Tumor cell lines; Tumor cells; Tumors; Urinary bladder; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Viability; Wound Healing - genetics; Xenografts; Ann Arbor Michigan; United States > US; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0150138

ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable therapeutic target in patients with advanced disease.