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Supplementary Figure S1 from The Antipsychotic Drug Penfluridol Inhibits N-Linked Glycoprotein Processing and Enhances T-cell–Mediated Tumor Immunity

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posted on 2024-05-02, 07:45 authored by Wenlong Xu, Yuqi Wang, Na Zhang, Xiaofeng Lin, Di Zhu, Cheng Shen, Xiaobo Wang, Haiyang Li, Jinjiang Xue, Qian Yu, Xinyi Lu, Lu Zhou, Qingli He, Zhijun Tang, Shaodan He, Jianjun Fan, Jianbo Pan, Jiangjiang Tang, Wei Jiang, Mingliang Ye, Fanghui Lu, Zengxia Li, Yongjun Dang

(a) Western blot analysis of glycoprotein patterns in MDA-MB-231 cells after treatment with the indicated concentrations of penfluridol for 24 hours. Red arrowhead, immature glycoproteins. (b) Western blot analysis of protein expression pattern of ACE2 in HEK293T cells after treatment with the indicated concentrations of penfluridol for 24 hours. (c) In HEK293T cells, FLAG-tagged ACE2 was treated for 24 hours, collected by immunoprecipitation, subjected to SDS-PAGE, and analyzed by western blot. (d) Pearson correlation coefficient of three independent groups of (c) through N-glycan profiling.

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ARTICLE ABSTRACT

Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more saccharide-structure-perturbing compounds, a repurposed drug screen by using a library consisting of 1530 FDA-approved drugs was performed. Interestingly, an antipsychotic drug, penfluridol, was identified as being able to decrease cell surface wheat germ agglutinin staining. In the presence of penfluridol, cell membrane glycoproteins programmed death-ligand 1 (PD-L1) shifted to a lower molecular weight. Further studies demonstrated that penfluridol treatment caused an accumulation of high-mannose oligosaccharides, especially Man5–7GlcNAc2 glycan structures. Mechanistically, this effect is due to direct targeting of MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation. Moreover, we found that altered glycosylation of PD-L1 caused by penfluridol disrupted interactions between programmed cell death protein 1 and PD-L1, resulting in activation of T-cell tumor immunity. In a mouse xenograft and glioma model, penfluridol enhanced the antitumor effect of the anti–PD-L1 antibody in vivo. Overall, these findings revealed an important biological activity of the antipsychotic drug penfluridol as an inhibitor of glycan processing and proposed a repurposed use of penfluridol in antitumor therapy through activation of T-cell immunity.