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ACS Cent Sci. 2015 Jul 22;1(4):181-190. Epub 2015 Jul 13.

Human Cancer Antigen Globo H Is a Cell-Surface Ligand for Human Ribonuclease 1.

Author information

1
Department of Biochemistry, National Magnetic Resonance Facility at Madison, and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
2
Department of Biochemistry, National Magnetic Resonance Facility at Madison, and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States ; Department of Biochemistry, National Magnetic Resonance Facility at Madison, and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
3
Organic Synthesis Core Facility and Laboratory for Bioorganic Chemistry, Memorial Sloan Kettering Cancer Center , New York, New York 10021, United States.
4
Organic Synthesis Core Facility and Laboratory for Bioorganic Chemistry, Memorial Sloan Kettering Cancer Center , New York, New York 10021, United States ; Department of Chemistry, Columbia University , New York, New York 10027, United States.

Abstract

Pancreatic-type ribonucleases are secretory enzymes that catalyze the cleavage of RNA. Recent efforts have endowed the homologues from cow (RNase A) and human (RNase 1) with toxicity for cancer cells, leading to a clinical trial. The basis for the selective toxicity of ribonuclease variants for cancerous versus noncancerous cells has, however, been unclear. A screen for RNase A ligands in an array of mammalian cell-surface glycans revealed strong affinity for a hexasaccharide, Globo H, that is a tumor-associated antigen and the basis for a vaccine in clinical trials. The affinity of RNase A and RNase 1 for immobilized Globo H is in the low micromolar-high nanomolar range. Moreover, reducing the display of Globo H on the surface of human breast adenocarcinoma cells with a small-molecule inhibitor of biosynthesis or a monoclonal antibody antagonist decreases the toxicity of an RNase 1 variant. Finally, heteronuclear single quantum coherence (HSQC) NMR spectroscopy showed that RNase 1 interacts with Globo H by using residues that are distal from the enzymic active site. The discovery that a systemic human ribonuclease binds to a moiety displayed on human cancer cells links two clinical paradigms and suggests a mechanism for innate resistance to cancer.

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