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.
Keywords:
LOPAC1280; QSOX1; ebselen; pancreatic cancer; renal cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Azoles / chemistry
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Azoles / pharmacology*
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Blotting, Western
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Carcinoma, Renal Cell / drug therapy*
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cysteine / antagonists & inhibitors
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Cysteine / genetics
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Cysteine / metabolism
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Humans
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Isoindoles
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Kidney Neoplasms / drug therapy*
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Mice, Nude
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Molecular Sequence Data
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Molecular Structure
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Neoplasm Invasiveness
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Organoselenium Compounds / chemistry
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Organoselenium Compounds / pharmacology*
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Oxidoreductases Acting on Sulfur Group Donors / antagonists & inhibitors
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Oxidoreductases Acting on Sulfur Group Donors / genetics
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Oxidoreductases Acting on Sulfur Group Donors / metabolism*
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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RNA Interference
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Sequence Homology, Amino Acid
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Azoles
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Isoindoles
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Organoselenium Compounds
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ebselen
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Oxidoreductases Acting on Sulfur Group Donors
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QSOX1 protein, human
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Cysteine