Molecular Inhibitor of QSOX1 Suppresses Tumor Growth In Vivo

• Published in: Molecular cancer therapeutics 2020-01, Vol.19 (1), p.112-122
• Main Authors: Fifield, Amber L, Hanavan, Paul D, Faigel, Douglas O, Sergienko, Eduard, Bobkov, Andrey, Meurice, Nathalie, Petit, Joachim L, Polito, Alysia, Caulfield, Thomas R, Castle, Erik P, Copland, John A, Mukhopadhyay, Debabrata, Pal, Krishnendu, Dutta, Shamit K, Luo, Huijun, Ho, Thai H, Lake, Douglas F
• Format: Article
• Language: English
• Subjects: Animals; Female; Gene Expression Regulation, Neoplastic - genetics; Humans; Kidney Neoplasms - drug therapy; Mice; Mice, SCID; Oxidoreductases Acting on Sulfur Group Donors - therapeutic use
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-19-0233

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion and , we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as "SBI-183," suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1.