硼替佐米
下调和上调
福克斯A1
癌症研究
细胞凋亡
蛋白酶体抑制剂
乳腺癌
癌细胞
蛋白酶体
癌症
化学
生物
医学
细胞生物学
内科学
生物化学
基因
多发性骨髓瘤
作者
Yubo Liu,Handong Wang,Tong Zhu,Nana Zhang,Lingyan Wang,Tianmiao Huang,Yu Cao,Wenli Li,Jianing Zhang
摘要
Abstract Bortezomib (BTZ), a well‐established proteasome inhibitor used in the clinical therapy, leads the modulation of several biological alterations and in turn induces apoptosis. Although clinical trials with BTZ have shown promising results for some types of cancers, but not for some others, including those of the breast. The molecular basis of BTZ resistance in breast cancer remains elusive. In the present study, we found that cellular O‐GlcNAc modification was dramatically elevated by BTZ treatment in intrinsic resistant MCF‐7 and T47D cells, but not in sensitive MDA‐MB‐231 cells. A progressive increase in O‐GlcNAcylation characterized the increased acquired resistance of MDA‐MB‐231‐derived cells. We showed that elevated O‐GlcNAc subsequently modified breast cancer related pioneer factor FOXA1 and reduced its protein stability. Further, we demonstrated that FOXA1 attenuation was involved in transcriptional downregulation of proapoptotic Bim and thus suppressed breast cancer cell apoptosis. Finally, the combination of O‐GlcNAc inhibitor L01 to BTZ sensitized resistant cells. Our results have revealed a new regulatory mechanism that involves O‐GlcNAc elevation mediated Bim deficiency, which plays a key role in the apoptotic dysregulation and BTZ resistance in breast cancer cells.
科研通智能强力驱动
Strongly Powered by AbleSci AI