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.
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Cell Chem Biol. 2017 Feb 16;24(2):149-158. doi: 10.1016/j.chembiol.2016.12.009. Epub 2017 Jan 12.
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.
虽然人们对小分子化疗药物的耐药性进行了深入研究，但肿瘤细胞逃避膜溶解化合物破坏的潜力仍未被探索。抗癌肽（ACPs）是一类通过快速和非立体特异性机制破坏肿瘤细胞膜的药物，这使得人们认为细胞对 ACP 的耐药性不太可能发生。我们证明，真核细胞确实可以对模型溶瘤肽 SVS-1 产生耐药性，SVS-1 优先破坏癌细胞的膜。利用裂殖酵母作为模型生物，我们表明 ACP 耐药性主要通过细胞表面阴离子糖的丢失来控制。在哺乳动物癌细胞中也发现了类似的机制，其中负电荷唾液酸残基的去除直接将 SVS-1 敏感的细胞系转化为耐药表型。这些结果表明，细胞表面糖基化的变化在肿瘤细胞对溶瘤肽的耐药性中起着重要作用。
