The Antipsychotic Drug Penfluridol Inhibits N-Linked Glycoprotein Processing and Enhances T-cell-Mediated Tumor Immunity

作者全名：Xu, Wenlong; Wang, Yuqi; Zhang, Na; Lin, Xiaofeng; Zhu, Di; Shen, Cheng; Wang, Xiaobo; Li, Haiyang; Xue, Jinjiang; Yu, Qian; Lu, Xinyi; Zhou, Lu; He, Qingli; Tang, Zhijun; He, Shaodan; Fan, Jianjun; Pan, Jianbo; Tang, Jiangjiang; Jiang, Wei; Ye, Mingliang; Lu, Fanghui; Li, Zengxia; Dang, Yongjun

作者地址：[Xu, Wenlong; Wang, Yuqi; Lin, Xiaofeng; Wang, Xiaobo; Yu, Qian; Lu, Xinyi; Jiang, Wei; Li, Zengxia] Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Sch Basic Med Sci,Key Lab Metab & Mol Med,Minist E, Shanghai, Peoples R China; [Zhang, Na; Ye, Mingliang] Chinese Acad Sci, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China; [Zhu, Di] Fudan Univ, Lab Tumor Immunol, Dept Human Anat Histol & Embryol, Basic Med Sch, Shanghai, Peoples R China; [Shen, Cheng; Tang, Jiangjiang] Northwest A&F Univ, Coll Chem & Pharm, Shaanxi Key Lab Nat Prod & Chem Biol, Yangling, Shaanxi, Peoples R China; [Li, Haiyang; He, Qingli] Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Res Ctr Chiral Drugs, Shanghai, Peoples R China; [Xue, Jinjiang; Zhou, Lu; Lu, Fanghui] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Tang, Zhijun] Chinese Acad Sci, State Key Lab Bioorgan & Nat Prod Chem, Shanghai Inst Organ Chem, Shanghai, Peoples R China; [He, Shaodan; Fan, Jianjun; Pan, Jianbo; Dang, Yongjun] Chongqing Med Univ, Affiliated Hosp 1, Basic Med Res & Innovat Ctr Novel Target & Therape, Inst Life Sci,Minist Educ, Chongqing, Peoples R China; [Lu, Fanghui; Dang, Yongjun] 1 Med Sch Rd, Chongqing, Peoples R China; [Li, Zengxia] A4018, Bldg 2, Sci Res Bldg, 131 Dongan Rd, Shanghai, Peoples R China; [Ye, Mingliang] Biotechnol Dept, Room 414,Grp 1809,457 Zhongshan Rd, Dalian, Peoples R China; [Jiang, Wei] A4-030, Bldg 2, Sci Res Bldg, 131 Dongan Rd, Shanghai, Peoples R China

通信作者：Lu, FH; Dang, YJ (通讯作者)，1 Med Sch Rd, Chongqing, Peoples R China.; Li, ZX (通讯作者)，A4018, Bldg 2, Sci Res Bldg, 131 Dongan Rd, Shanghai, Peoples R China.; Ye, ML (通讯作者)，Biotechnol Dept, Room 414,Grp 1809,457 Zhongshan Rd, Dalian, Peoples R China.; Jiang, W (通讯作者)，A4-030, Bldg 2, Sci Res Bldg, 131 Dongan Rd, Shanghai, Peoples R China.

来源：MOLECULAR CANCER THERAPEUTICS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001225909800004

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：23

期号：5

开始页：648

结束页：661

文献类型：Article

关键词：　

摘要：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.

基金机构：n/a [2022YFC2804800]; National Key Research and Development Program of China [22137002, 21877016, 81820108030, 81772962, 92253305, 82273021, 81972621]; National Natural Science Foundation of China [20JC1410900]; Science and Technology Commission of Shanghai Municipality [CXQT21016]; University Innovation Research Group in Chongqing [CQYC20200302119]; Chongqing Talent Program Project; High-Level Innovation Platform Cultivation Plan of Chongqing; Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing; Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning

基金资助正文：This work was supported by the National Key Research and Development Program of China (No.2022YFC2804800, to W. Jiang), the National Natural Science Foundation of China (no. 22137002, 21877016, to Y. Dang; 81820108030, 81772962, to Z. Li; 92253305, 82273021, 81972621, to W. Jiang), Science and Technology Commission of Shanghai Municipality (Grant 20JC1410900, to Y. Dang), University Innovation Research Group in Chongqing (No. CXQT21016, to Y. Dang), Chongqing Talent Program Project (No. CQYC20200302119, to Y. Dang), High-Level Innovation Platform Cultivation Plan of Chongqing (to Y. Dang), Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing (to Y. Dang) and Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (to W. Jiang).