Human Cancer Antigen Globo H Is a Cell-Surface Ligand for Human Ribonuclease 1
| Autor: | Guangbin Yang, Samuel J. Danishefsky, Ouathek Ouerfelli, Chelcie H. Eller, Tzu-Yuan Chao, John L. Markley, Ronald T. Raines, Kiran Kumar Singarapu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0303 health sciences
biology medicine.drug_class RNase P General Chemical Engineering RNA General Chemistry Monoclonal antibody 3. Good health lcsh:Chemistry 03 medical and health sciences 0302 clinical medicine lcsh:QD1-999 Biochemistry Antigen 030220 oncology & carcinogenesis Cancer cell Immunology medicine biology.protein Ribonuclease RNase H Heteronuclear single quantum coherence spectroscopy 030304 developmental biology Research Article |
| Zdroj: | ACS Central Science ACS Central Science, Vol 1, Iss 4, Pp 181-190 (2015) |
| ISSN: | 2374-7951 2374-7943 |
| Popis: | 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. A systemic human ribonuclease, which can be cytotoxic, binds to a glycan displayed on human cancer cells, linking two clinical paradigms and suggesting a mechanism for innate resistance to cancer. |
| Databáze: | OpenAIRE |
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