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.