title: Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer Peptide.
abstract: Although resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Anticancer peptides (ACPs) are a class of such agents that disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance toward ACPs is unlikely to occur. We demonstrate that eukaryotic cells can, indeed, develop resistance to the model oncolytic peptide SVS-1, which preferentially disrupts the membranes of cancer cells. Utilizing fission yeast as a model organism, we show that ACP resistance is largely controlled through the loss of cell-surface anionic saccharides. A similar mechanism was discovered in mammalian cancer cells where removal of negatively charged sialic acid residues directly transformed SVS-1-sensitive cell lines into resistant phenotypes. These results demonstrate that changes in cell-surface glycosylation play a major role in tumor cell resistance toward oncolytic peptides.
authors.affiliation: Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Medina
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address: joel.schneider@nih.gov.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Schneider
authors.affiliation: Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address: klara@mail.nih.gov.
authors.forename: Amar J S
authors.initials: AJS
authors.lastname: Klar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006031:Glycosylation; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011134:Polysaccharides / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011134:Polysaccharides; C574293:SVS-1 peptide
keywords: anticancer peptides; cancer cell resistance; genetics; glycosylation; membrane-lytic peptides