NDRG2 Activates Endoplasmic Reticulum Stress via IRE1α-XBP1 to Reverse Tamoxifen Resistance in ER+Breast Cancer
10.13865/j.cnki.cjbmb.2024.09.1182
- VernacularTitle:NDRG2调控IRE1α-XBP1介导内质网应激逆转ER+乳腺癌他莫昔芬耐药
- Author:
Shou-Ying WANG
1
;
Yan-Yan DU
;
Peng CAO
;
Wen-Yu LIU
;
Jun-Yu QI
;
Wei-Ye SHI
;
Chun-Xiao ZHANG
;
Xiao-Lei ZHOU
Author Information
1. 河北科技大学食品与生物学院,石家庄 050091
- Keywords:
estrogen receptor(ER+)breast cancer;
N-myc downstream-regulated gene 2(NDRG2);
tamoxifen(TAM);
drug resistance;
endoplasmic reticulum stress(ERS)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2024;40(10):1409-1416
- CountryChina
- Language:Chinese
-
Abstract:
Tamoxifen(TAM)has been widely used for the treatment of ER+breast cancer.However,the inevitable emergence of resistance to tamoxifen obstructs the successful treatment of this cancer.The tumor suppressor gene N-myc downstream-regulated gene 2(NDRG2)plays a significant role in the de-velopment of ER+breast cancer.However,it is unclear whether NDRG2 participates in mediating TAM resistance in ER+breast cancer.Here,we investigate the expression of NDRG2 mRNA and protein in TAM-sensitive and TAM-resistant ER+breast cancer cells.The results of immunoblotting experiments re-vealed a negative correlation between NDRG2 expression and TAM resistance ability in ER+breast cancer cells(P＜0.001).CCK-8 cell viability assays and soft agar colony formation assays showed that NDRG2 overexpression in TAM resistant cells significantly reduced the TAM IC50 value and the soft agar colony formation rate(P＜0.001).For the mechanism,the ERAD reporter protein assays showed that NDRG2 overexpression upregulated the expression of the ERAD reporter protein CD3ε-YFP and increased the lev-els of spliced XBP1s mRNA,leading to severe endoplasmic reticulum stress in TAM resistant cells(P＜0.001).Immunoblot analysis confirmed that overexpression of NDRG2 significantly increased the level of phosphorylation of the endoplasmic reticulum stress sensor IRE 1α and the expression levels of its down-stream protein factors,including ERdj4,P58IPK,EDEM and PDIA5(P＜0.001).The in vivo xenograft tumor experiments in mice further verified that NDRG2 overexpression significantly inhibited the growth of resistant tumors,which enhanced the therapeutic effect of TAM(P＜0.001).These findings indicate that increasing NDRG2 expression and triggering severe endoplasmic reticulum stress upon TAM treatment can reverse the resistance of ER+breast cancer cells to TAM and inhibits the growth of ER+breast canc-er tumors.Our results provide valuable new insights and potential targets for improving the clinical man-agement of TAM-resistance and prognosis in ER+breast cancer.
