A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis.
A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis.
复制标题
一种新型 HIF-2α 靶向抑制剂通过 SOD2-mtROS-PDI/GPR78-UPRER 轴抑制缺氧诱导的乳腺癌干性
DOI：
10.1038/s41418-022-00963-8
复制
发表时间：
2022-09
影响因子：
12.4
通讯作者：
Wei, Minjie
中科院分区：
文献类型：
--
作者：
Yan, Yuanyuan;He, Miao;Zhao, Lin;Wu, Huizhe;Zhao, Yanyun;Han, Li;Wei, Binbin;Ye, Dongman;Lv, Xuemei;Wang, Yan;Yao, Weifan;Zhao, Haishan;Chen, Bo;Jin, Zining;Wen, Jian;Zhu, Yan;Yu, Tao;Jin, Feng;Wei, Minjie
低分化肿瘤微环境（TME）在乳腺癌中诱导肿瘤干细胞样表型并导致化疗耐药中起关键作用。然而，乳腺癌细胞（BC）的干细胞重编程的机制仍然是未知的。本研究表明HIF-2α（而非HIF-1α）通过SOD 2-mtROS-PDI/GRP 78-UPRER途径诱导低氧条件下BCs的干性，并通过线粒体活性氧（mtROS）水平将线粒体代谢状态与内质网（ER）反应联系起来。HIF-2α激活药物敏感MCF 7和T47 D细胞内质网未折叠蛋白反应（UPRER）诱导耐药干细胞样表型HIF-2α的基因缺失或药物抑制（YQ-0629）可在体外和体内消除缺氧诱导的干细胞样表型。HIF-2α在缺氧条件下激活超氧化物歧化酶2（SOD 2）的转录，从而降低线粒体ROS水平。随着较少的mtROS转运到内质网，蛋白质二硫键异构酶（PDI）的表达和活性被抑制，允许葡萄糖调节蛋白78（GRP 78）从UPRER的受体蛋白解离并结合错误折叠的蛋白以激活UPRER，这最终赋予BC化学抗性和干细胞样特性。此外，由HIF-2α敲低和随后的UPER抑制引起的mtROS和PDI水平的增加可以通过mitoTEMPOL（mtROS清除剂）、16 F16（PDI抑制剂）或GRP 78过表达而基本上得到挽救。总之，我们报道了HIF-2α-SOD 2-mtROS-PDI/GRP 78-UPRER轴在介导低氧诱导的BCs干性中的关键作用，突出了细胞器之间的相互作用，并为进一步开发靶向HIF-2α抑制剂作为化疗耐药乳腺癌的有希望的治疗策略提供了证据。
Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPRER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPRER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPRER and bind misfolded protein to activate UPRER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPRER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPRER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.
登录
查看更多内容
影响因子：
9
作者：
Chang CW;Chen YS;Tsay YG;Han CL;Chen YJ;Yang CC;Hung KF;Lin CH;Huang TY;Kao SY;Lee TC;Lo JF
通讯作者：
Lo JF
影响因子：
8.8
作者：
Johansson, Elinn;Grassi, Elisa S.;Pietras, Alexander
通讯作者：
Pietras, Alexander
影响因子：
4
作者：
Eletto, Davide;Chevet, Eric;Appenzeller-Herzog, Christian
通讯作者：
Appenzeller-Herzog, Christian
影响因子：
21.3
作者：
Liu, Lu;Zhao, Meiling;Li, Qing
通讯作者：
Li, Qing
影响因子：
16.6
作者：
Cazet AS;Hui MN;Elsworth BL;Wu SZ;Roden D;Chan CL;Skhinas JN;Collot R;Yang J;Harvey K;Johan MZ;Cooper C;Nair R;Herrmann D;McFarland A;Deng N;Ruiz-Borrego M;Rojo F;Trigo JM;Bezares S;Caballero R;Lim E;Timpson P;O'Toole S;Watkins DN;Cox TR;Samuel MS;Martín M;Swarbrick A
通讯作者：
Swarbrick A