Targeting and Suppression of Survivin in Cancer Cells Based on the Interaction of Cell Surface Vimentin with N‑Acetylglucosamine-Bearing Polymers.

Survivin, a protein overexpressed in various fetal and malignant tumor tissues, induces tumor progression and resistance to cancer therapy. Cell surface vimentin has N-acetylglucosamine (GlcNAc)-binding activities in several cell types including tumor cells. Furthermore, GlcNAc-bearing polymers downregulate the expression of the survivin-encoding baculoviral inhibitor of apoptosis protein repeat-containing protein 5 (BIRC5). Thus, cell surface vimentin is a target for cancer therapy. The downregulation of survivin expression in cancer cells by selectively targeting cell surface vimentin with GlcNAc-bearing polymers may mitigate drug resistance. However, the ability of GlcNAc to bind to cell surface vimentin depends on its valency in GlcNAc-bearing polymers. The optimal GlcNAc valency for the interaction remains unknown. Therefore, we aimed to develop optimal GlcNAc-bearing polymers for effective cancer therapy. In this study, GlcNAc polymers of various lengths were synthesized through reversible addition/fragmentation chain-transfer polymerization. We found that a low-molecular-weight GlcNAc polymer (5 GlcNAc-mer) interacted with cell surface vimentin-expressing cells to a greater extent than high-molecular-weight GlcNAc polymers (10 and 20 GlcNAc-mer). These interactions upregulated the expression of p53, an upstream signal transducer. Moreover, they inhibited the phosphorylation of signal transducers and activators of transcription 3 and downregulated survivin expression. In addition, low-molecular-weight GlcNAc polymers decreased the viability of 3LL cells, mouse lung carcinoma cell lines, and MCF-7 cells, human breast cancer lines, but not that of MCF10A, nontumorigenic breast cells. These findings suggest that low-molecular-weight GlcNAc polymers, which selectively target cancer cells and downregulate survivin expression, are promising tools for cancer therapy.