MUC1-C is a target of salinomycin in inducing ferroptosis of cancer stem cells.
MUC1-C is a target of salinomycin in inducing ferroptosis of cancer stem cells.
复制标题
MUC 1-C是盐霉素诱导肿瘤干细胞铁凋亡的靶点。
DOI：
10.1038/s41420-023-01772-9
复制
发表时间：
2024-01-05
影响因子：
7
通讯作者：
Kufe, Donald W.
中科院分区：
文献类型：
--
作者：
Daimon, Tatsuaki;Bhattacharya, Atrayee;Wang, Keyi;Haratake, Naoki;Nakashoji, Ayako;Ozawa, Hiroki;Morimoto, Yoshihiro;Yamashita, Nami;Kosaka, Takeo;Oya, Mototsugu;Kufe, Donald W.
致癌MUC1-C跨膜蛋白是癌症干细胞（CSC）状态的关键效应因子。人类癌症发展过程中对MUC1-C的自我更新依赖强调了开发抗MUC1-C药物的必要性。然而，目前还没有批准的靶向muc1 - c依赖性csc的小分子药物。在筛选小分子时，我们发现盐霉素（SAL）是一种铁下垂的诱诱剂，是MUC1-C信号传导的有效抑制剂。我们证明SAL通过破坏NF-κB/MUC1-C自感应电路来抑制MUC1-C的表达，这是铁下垂抵抗所必需的。我们的研究结果表明，sal诱导的MUC1-C抑制下调MUC1-C→MYC通路，该通路激活编码(i)谷胱甘肽二硫还原酶（GSR）和（ii） LDL受体相关蛋白8 （LRP8）的基因，它们分别通过产生GSH和调节硒水平来抑制铁死亡。GSR和LRP8参与谷胱甘肽过氧化物酶4 （GPX4）的功能，GPX4是铁致细胞死亡的重要负调节因子。我们证明，基因靶向MUC1-C或与GO-203肽抑制剂一起抑制GPX4表达和GPX活性，这与铁下垂的诱导有关。对连续传代富集的CSCs作为肿瘤球的研究进一步表明，SAL的作用是通过下调MUC1-C介导的，从而克服对铁凋亡的抗性。作为这些结果的证实，MUC1-C细胞质结构域的MUC1-C下调(i)逆转了GSR、LRP8和GPX4表达的抑制，（ii）减弱了铁下垂的诱导。这些发现表明SAL是MUC1-C信号的独特小分子抑制剂，并证明MUC1-C是铁下垂抗性的重要效应物。
The oncogenic MUC1-C transmembrane protein is a critical effector of the cancer stem cell (CSC) state. Addiction to MUC1-C for self-renewal in the progression of human cancers has emphasized the need for development of anti-MUC1-C agents. However, there are presently no approved small molecules for targeting MUC1-C-dependent CSCs. In screening for small molecules, we identified salinomycin (SAL), an inducer of ferroptosis, as a potent inhibitor of MUC1-C signaling. We demonstrate that SAL suppresses MUC1-C expression by disrupting a NF-κB/MUC1-C auto-inductive circuit that is necessary for ferroptosis resistance. Our results show that SAL-induced MUC1-C suppression downregulates a MUC1-C→MYC pathway that activates genes encoding (i) glutathione-disulfide reductase (GSR), and (ii) the LDL receptor related protein 8 (LRP8), which inhibit ferroptosis by generating GSH and regulating selenium levels, respectively. GSR and LRP8 contribute to the function of glutathione peroxidase 4 (GPX4), an essential negative regulator of ferroptotic cell death. We demonstrate that targeting MUC1-C genetically or with the GO-203 peptide inhibitor suppresses GPX4 expression and GPX activity in association with the induction of ferroptosis. Studies of CSCs enriched by serial passage as tumorspheres further demonstrate that the effects of SAL are mediated by downregulation of MUC1-C and thereby overcoming resistance to ferroptosis. As confirmation of these results, rescue of MUC1-C downregulation with the MUC1-C cytoplasmic domain (i) reversed the suppression of GSR, LRP8 and GPX4 expression, and (ii) attenuated the induction of ferroptosis. These findings identify SAL as a unique small molecule inhibitor of MUC1-C signaling and demonstrate that MUC1-C is an important effector of resistance to ferroptosis.
登录
查看更多内容
DOI：
10.1158/1541-7786.mcr-21-0672
发表时间：
2022-04-01
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Bhattacharya A;Fushimi A;Yamashita N;Hagiwara M;Morimoto Y;Rajabi H;Long MD;Abdulla M;Ahmad R;Street K;Liu S;Liu T;Kufe D
通讯作者：
Kufe D
影响因子：
11.5
作者：
Hasegawa, Masanori;Sinha, Raj Kumar;Kufe, Donald
通讯作者：
Kufe, Donald
抗MUC1-C抗体偶联的纳米颗粒增强了分离放射疗法的功效。
DOI：
10.1016/j.ijrobp.2020.06.069
发表时间：
2020-12-01
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
Detappe A;Mathieu C;Jin C;Agius MP;Diringer MC;Tran VL;Pivot X;Lux F;Tillement O;Kufe D;Ghoroghchian PP
通讯作者：
Ghoroghchian PP
影响因子：
5.2
作者：
通讯作者：
--
影响因子：
14.8
作者：
Li, Zhipeng;Ferguson, Lucas;Deol, Kirandeep K.;Roberts, Melissa A.;Magtanong, Leslie;Hendricks, Joseph M.;Mousa, Gergey Alzaem;Kilinc, Seda;Schaefer, Kaitlin;Wells, James A.;Bassik, Michael C.;Goga, Andrei;Dixon, Scott J.;Ingolia, Nicholas T.;Olzmann, James A.
通讯作者：
Olzmann, James A.