STT3-mediated aberrant N-glycosylation of CD24 inhibits paclitaxel sensitivity in triple-negative breast cancer  

作　　者：Jun Wang Hui-min Zhang Guan-hua Zhu Li-li Zhao Ji Shi Zhou-tong Dai Jia-peng Li Xing-rui Li Fan Sun Yuan Wu Shao-yong Chen Han-ning Li Xing-hua Liao Yuan Xiang 

机构地区：[1]Institute of Biology and Medicine,College of Life and Health Sciences,Wuhan University of Science and Technology,Wuhan,430081,China [2]Department of Materials Science,Wuhan University of Science and Technology,Wuhan,430081,China [3]Department of Human Anatomy&Histoembryology,School of Basic Medical sciences,Xinxiang Medical University,Xinxiang,453000,China [4]Department of Gynaecological Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [5]Department of Thyroid and Breast Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [6]Department of Radiation Oncology,Hubei Cancer Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430079,China [7]Department of Medical Laboratory,Tongji Medical College,Central Hospital of Wuhan,Huazhong University of Science and Technology,Wuhan,430014,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1097-1110,共14页中国药理学报(英文版)

基　　金：financially supported by the National Natural Science Foundation of China(32170578 and 82203497);Hubei Natural Science Foundation(2024AFB905 and 2024AFD011);Hubei Province Key R&D Program(2022BCA007);Department of Education Scientific Research Program guidance project(B2023014);“The 14th Five Year Plan”Hubei Provincial advantaged characteristic disciplines(groups)project of Wuhan University of Science and Technology(2023C0303);Natural Science Foundation Exploration Program of Wuhan(2024040801020310);the Hunan Natural Science Foundation(2023JJ50310 and 2023JJ50296).

摘　　要：Paclitaxel is one of the main chemotherapic medicines against triple-negative breast cancer(TNBC)in clinic.However,it has been perplexed by paclitaxel resistance in TNBC patients,resulting in a poor prognosis.Abnormal protein glycosylation is closely related to the occurrence and progression of tumors and malignant phenotypes such as chemotherapy resistance.CD24 is a highly glycosylated membrane protein that is highly expressed in TNBC,leading to tumorigenesis and poor prognosis.In this study we investigated the relationship between abnormal glycosylation of CD24 and paclitaxel susceptibility in TNBC and the molecular mechanisms.We showed that CD24 protein levels were significantly up-regulated in both TNBC tissues and cells,and CD24 protein was highly glycosylated.Genetic and pharmacological inhibition of N-glycosylation of CD24 enhances the anticancer activity of paclitaxel in vitro and tumor xenograft models.We revealed that the molecular mechanism of N-glycosylation of CD24 in paclitaxel resistance involved inhibition of ferroptosis,a new form that regulates cell death.Inhibition of N-glycosylation of CD24 increased glutathione consumption,iron content,and lipid peroxidation,resulting in paclitaxel-induced ferroptosis.We demonstrated that endoplasmic reticulum(ER)-associated glycosyltransferase STT3 isoforms(including both STT3A and STT3B isoforms)enable N-glycosylation of the L-asparagine(N)site.Knockout of the endogenous STT3 isoform in TNBC cells partially reduced the glycosylation status of CD24.Our results demonstrate the critical role of N-glycosylation of CD24 in weakening drug sensitivity by inhibiting ferroptosis,highlighting new insights that targeting N-glycosylation of CD24 has great potential to promote chemotherapy sensitivity and efficacy.

关 键 词：triple-negative breast cancer PACLITAXEL CD24 N-GLYCOSYLATION ferroptosis STT3 

分 类 号：R737.9[医药卫生—肿瘤]