Synthetic Retinoid Kills Drug-Resistant Cancer Stem Cells via Inducing RARγ-Translocation-Mediated Tension Reduction and Chromatin Decondensation.
Synthetic Retinoid Kills Drug-Resistant Cancer Stem Cells via Inducing RARγ-Translocation-Mediated Tension Reduction and Chromatin Decondensation.
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合成类维生素A通过诱导RARγ-易位-介导的张力降低和染色质解凝来杀死耐药性癌症干细胞
DOI：
10.1002/advs.202203173
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发表时间：
2022-11
期刊：
影响因子：
15.1
通讯作者：
Chen, Junwei
中科院分区：
文献类型：
--
作者：
Zhang, Yao;Dong, Qi;An, Quanlin;Zhang, Chumei;Mohagheghian, Erfan;Niu, Bing;Qi, Feng;Wei, Fuxiang;Chen, Sihan;Chen, Xinman;Wang, Anqi;Cao, Xin;Wang, Ning;Chen, Junwei
最近开发的合成类视黄醇可消除耐药恶性癌症干细胞样细胞的增殖并诱导其凋亡。然而，合成类视黄醇如何诱导癌症干细胞样细胞肿瘤再生细胞（TRC）凋亡的潜在机制尚不清楚。研究表明，虽然类视黄醇和传统抗癌药物顺铂、全反式视黄酸和他扎罗汀在诱导 TRC 凋亡之前都会抑制细胞骨架张力和染色质解浓缩，但类视黄醇的半最大抑制浓度比这些抗癌药物低 20 倍。合成的类维生素A诱导视黄酸受体γ（RARγ）从细胞核易位到细胞质，导致RARγ与Cdc42启动子的结合减少和Cdc42下调，从而减少丝状肌动蛋白（F-肌动蛋白）并抑制细胞骨架张力。提高 F-肌动蛋白或上调组蛋白 3 赖氨酸 9 三甲基化可减少视黄醇诱导的 DNA 损伤和 TRC 凋亡。染色质解缩分子和类视黄醇的组合治疗比单独使用合成类视黄醇更有效地抑制小鼠体内的肿瘤转移。这些发现提出了一种降低细胞张力和解凝结染色质的策略，以增强 DNA 损伤，从而高效地消除癌症干细胞样细胞的转移。靶向治疗是癌症的主要治疗方法之一，但抗癌药物的耐药性阻碍了其在多种恶性肿瘤中的应用。结果表明，合成类视黄醇WYC-209克服了传统抗癌药物的局限性，通过激活视黄酸受体γ从细胞核退出，诱导张力消除介导的染色质解缩和DNA损伤，从而有效杀死恶性肿瘤。
A recently developed synthetic retinoid abrogates proliferation and induces apoptosis of drug‐resistant malignant‐cancer‐stem‐cell‐like cells. However, the underlying mechanisms of how the synthetic retinoid induces cancer‐stem‐cell‐like cell tumor‐repopulating cell (TRC) apoptosis are elusive. Here, it is shown that although the retinoid and conventional anticancer drugs cisplatin, all‐trans retinoic acid, and tazarotene all inhibit cytoskeletal tension and decondense chromatin prior to inducing TRC apoptosis, half‐maximal inhibitory concentration of the retinoid is 20‐fold lower than those anticancer drugs. The synthetic retinoid induces retinoic acid receptor gamma (RARγ) translocation from the nucleus to the cytoplasm, leading to reduced RARγ binding to Cdc42 promoter and Cdc42 downregulation, which decreases filamentous‐actin (F‐actin) and inhibits cytoskeletal tension. Elevating F‐actin or upregulating histone 3 lysine 9 trimethylation decreases retinoid‐induced DNA damage and apoptosis of TRCs. The combinatorial treatment with a chromatin decondensation molecule and the retinoid inhibits tumor metastasis in mice more effectively than the synthetic retinoid alone. These findings suggest a strategy of lowering cell tension and decondensing chromatin to enhance DNA damage to abrogate metastasis of cancer‐stem‐cell‐like cells with high efficacy. Targeted therapy is one of the primary treatments for cancer, but resistance to anticancer drugs hampers their application to many types of malignant tumors. It is shown that synthetic retinoid WYC‐209 overcomes the limitation of conventional anticancer drugs by activating retinoic acid receptor gamma exit from nucleus to induce tension‐abrogation‐mediated chromatin decondensation and DNA damage to effectively kill malignant tumors.
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影响因子：
5.4
作者：
Li Y;Seto E
通讯作者：
Seto E
影响因子：
4.6
作者：
Chen J;Zhou W;Jia Q;Chen J;Zhang S;Yao W;Wei F;Zhang Y;Yang F;Huang W;Zhang Y;Zhang H;Zhang Y;Huang B;Zhang Z;Jia H;Wang N
通讯作者：
Wang N
影响因子：
9
作者：
Mukherjee, Nabanita;Skees, Jenette;Shellman, Yiqun G.
通讯作者：
Shellman, Yiqun G.
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M
DNA损伤遵循修复因子耗竭，并预测孔迁移后癌细胞的基因组变异。
DOI：
10.1016/j.cub.2016.11.049
发表时间：
2017-01-23
期刊：
Current biology : CB
影响因子：
--
作者：
Irianto J;Xia Y;Pfeifer CR;Athirasala A;Ji J;Alvey C;Tewari M;Bennett RR;Harding SM;Liu AJ;Greenberg RA;Discher DE
通讯作者：
Discher DE