Prostatespecific membrane antigen PSMAmediated

Authors: Rebecca E Conway Camilo Rojas Jesse Alt Zora Nováková Spencer M Richardson Tori C Rodrick Julio L Fuentes Noah H Richardson Jonathan Attalla Samantha Stewart Beshoy Fahmy Cyril Barinka Mallika Ghosh Linda H Shapiro Barbara S Slusher

Publish Date: 2016/07/08

Volume: 19, Issue: 4, Pages: 487-500

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Abstract

Prostatespecific membrane antigen PSMA is a membranebound glutamate carboxypeptidase expressed in a number of tissues PSMA participates in various biological functions depending on the substrate available in the particular tissue in the brain PSMA cleaves the abundant neuropeptide Nacetylaspartylglutamate to regulate release of key neurotransmitters while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature where it regulates angiogenesis The previous research determined that PSMA cleavage of small peptides generated via matrix metalloproteasemediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells integrin signaling and angiogenesis although the specific peptide substrates were not identified Herein using enzymatic analyses and LC/MS we unequivocally demonstrate that several lamininderived peptides containing carboxyterminal glutamate moieties LQE IEE LNE are bona fide substrates for PSMA Subsequently the peptide products were tested for their effects on angiogenesis in various models We report that LQ the dipeptide product of PSMA cleavage of LQE efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo Importantly LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation E424S Endothelial cell activation by LQ was dependent on integrin beta1induced activation of focal adhesion kinase These results characterize a novel PSMA substrate provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapiesThis research was in part funded by a R01CA161056 to BSS and P01HL070694 to LHS and by BIOCEV CZ105/1100/020109 from the ERDF by RVO 86652036 and by 301/12/1513 from the Czech Science Foundation to ZN and CB The authors would like to thank Amber Bradley for her assistance with flow cytometry and the Lipscomb University Bioanalytical Core Lab for use of the flow cytometer We are grateful to Amanda D Williams and Margaret L Musick for their technical assistance

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