Ebselen inhibits QSOX1 enzymatic activity and suppresses invasion of pancreatic and renal cancer cell lines
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Paul D. Hanavan1, Chad R. Borges2, Benjamin A. Katchman2, Douglas O. Faigel3, Thai H. Ho3, Chen-Ting Ma4, Eduard A. Sergienko4, Nathalie Meurice3, Joachim L. Petit3, Douglas F. Lake1
1School of Life Sciences, Mayo Clinic Collaborative Research Building, Arizona State University, Scottsdale, AZ, USA
2Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
3Mayo Clinic Arizona, Scottsdale, AZ, USA
4Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
Douglas F. Lake, e-mail: email@example.com
Keywords: QSOX1, LOPAC1280, ebselen, renal cancer, pancreatic cancer
Received: March 26, 2015 Accepted: May 20, 2015 Published: June 01, 2015
Quiescin sulfhydryl oxidase 1 (QSOX1) is a highly conserved disulfide bond-generating enzyme that is overexpressed in diverse tumor types. Its enzymatic activity promotes the growth and invasion of tumor cells and alters extracellular matrix composition. In a nude mouse-human tumor xenograft model, tumors containing shRNA for QSOX1 grew significantly more slowly than controls, suggesting that QSOX1 supports a proliferative phenotype in vivo. High throughput screening experiments identified ebselen as an in vitro inhibitor of QSOX1 enzymatic activity. Ebselen treatment of pancreatic and renal cancer cell lines stalled tumor growth and inhibited invasion through Matrigel in vitro. Daily oral treatment with ebselen resulted in a 58% reduction in tumor growth in mice bearing human pancreatic tumor xenografts compared to controls. Mass spectrometric analysis of ebselen-treated QSOX1 mechanistically revealed that C165 and C237 of QSOX1 covalently bound to ebselen. This report details the anti-neoplastic properties of ebselen in pancreatic and renal cancer cell lines. The results here offer a “proof-of-principle” that enzymatic inhibition of QSOX1 may have clinical relevancy.
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