华中科技大学Yuan Xiang等研究人员合作发现，STT3介导的CD24异常N-糖基化抑制三阴性乳腺癌对紫杉醇的敏感性。相关论文于2024年12月12日在线发表于国际学术期刊《中国药理学报》。

研究人员探讨了CD24异常糖基化与三阴性乳腺癌（TNBC）紫杉醇敏感性之间的关系及其分子机制。研究人员发现CD24蛋白在TNBC组织和细胞中显著上调，且CD24蛋白高度糖基化。通过基因和药理学抑制CD24的N-糖基化，能够增强紫杉醇在体外和肿瘤异种移植模型中的抗癌活性。

研究人员揭示了CD24的N-糖基化在紫杉醇耐药中的分子机制，涉及抑制一种新的调控细胞死亡的方式——铁死亡。抑制CD24的N-糖基化增加了谷胱甘肽的消耗、铁含量和脂质过氧化，进而促进紫杉醇诱导的铁死亡。

研究人员证明了内质网（ER）相关糖基转移酶STT3同种型（包括STT3A和STT3B同种型）能够在L-天冬氨酸（N）位点进行N-糖基化。在TNBC细胞中敲除内源性STT3同种型会部分减少CD24的糖基化状态。这些结果表明，CD24的N-糖基化在通过抑制铁死亡来降低药物敏感性方面起着至关重要的作用，并强调了靶向CD24的N-糖基化在促进化疗敏感性和疗效方面的巨大潜力。

研究人员表示，紫杉醇是临床上用于治疗TNBC的主要化疗药物之一。然而，TNBC患者常常出现紫杉醇耐药性，导致预后不良。异常的蛋白糖基化与肿瘤的发生、发展以及化疗耐药等恶性表型密切相关。CD24是一种高度糖基化的膜蛋白，在三阴性乳腺癌中高表达，促使肿瘤发生并导致不良预后。

附：英文原文

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

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

Issue&Volume: 2024-12-12

Abstract: 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.

DOI: 10.1038/s41401-024-01419-0

Source: https://www.nature.com/articles/s41401-024-01419-0