Ebselen inhibits QSOX1 enzymatic activity and suppresses invasion of pancreatic and renal cancer cell lines

Paul D. Hanavan, Chad R. Borges, Benjamin A. Katchman, Douglas Orrick Faigel, Thai H Ho, Chen Ting Ma, Eduard A. Sergienko, Nathalie Meurice, Joachim L. Petit, Douglas F. Lake

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18418-18428
Number of pages11
JournalOncotarget
Volume6
Issue number21
StatePublished - 2015

Keywords

  • Ebselen
  • LOPAC1280
  • Pancreatic cancer
  • QSOX1
  • Renal cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Hanavan, P. D., Borges, C. R., Katchman, B. A., Faigel, D. O., Ho, T. H., Ma, C. T., Sergienko, E. A., Meurice, N., Petit, J. L., & Lake, D. F. (2015). Ebselen inhibits QSOX1 enzymatic activity and suppresses invasion of pancreatic and renal cancer cell lines. Oncotarget, 6(21), 18418-18428.