Supplementing sialic acid analogs overcomes radiotherapy resistance in triple-negative breast cancer by exacerbating ER stress

作者：Muwen Yang, Dongni Shi, Jianbo Lyu, Yulu Pan, Yiyang Lyv, Xiangfu Chen, Ying Ouyang, Yajie Liu, Yue Li, Libing Song · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103712 · 被引用次数：5 · 研究领域：Glycosylation and Glycoproteins Research、Endoplasmic Reticulum Stress and Disease、Natural product bioactivities and synthesis

Radiotherapy is a cornerstone treatment for triple-negative breast cancer (TNBC), and its incorporation has significantly delayed tumor recurrence. However, the emergence of radiotherapy resistance remains a major clinical challenge, substantially compromising treatment efficacy. Sialylation play a pivotal role in tumor therapeutic resistance which refers to the covalent linkage of sialic acids at the terminal ends of glycoproteins, a process catalyzed by a family of sialyltransferases. However, the function and mechanisms of sialylation in radiotherapy resistance remain elusive. In this study, upregulation of Galbeta1-4 GlcNAc alpha 2,3 sialyltransferase (ST3GAL4) was observed in association with sialylation in TNBC patients with radiotherapy resistance and predicted poorer survival. ST3GAL4 catalyzed α2,3-sialylation of HSP90B1, then facilitates its retrograde trafficking from the Golgi to ER mediated by SURF4 cargo receptor. ER-localized HSP90B1 accelerates the clearance of radiotherapy-induced misfolded proteins and upregulates the PERK-EIF2α-ATF4 pathway, which further transcriptionally upregulates antioxidant factors, such as SLC1A5, GCLC, and CTNS, to inhibit radiotherapy-induced ROS accumulation, ultimately leading to radiotherapy resistance, and poor clinical outcomes. Most importantly, sialic acid analogs (SAA) 3Fax-NeuAc inhibited the sialylation of HSP90B1 and its transport to the ER, thereby effectively overcomed radiotherapy resistance in TNBC. This study sugges...