Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.
Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.
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DOI：
10.1002/stem.1746
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发表时间：
2014-09
期刊：
影响因子：
5.2
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Choi, Dong Soon;Blanco, Elvin;Kim, Yoo-Shin;Rodriguez, Angel A.;Zhao, Hong;Huang, Tim Hui-Ming;Chen, Chun-Liang;Jin, Guangxu;Landis, Melissa D.;Burey, Lacey A.;Qian, Wei;Granados, Sergio M.;Dave, Bhuvanesh;Wong, Helen H.;Ferrari, Mauro;Wong, Stephen T. C.;Chang, Jenny C.
三阴性乳腺癌（TNBC）已知含有高比例的CD44⁺/CD24⁻/低表达的癌症干细胞（CSC），尽管进行了全身化疗，但其预后仍较差。氯喹（CQ）是一种抗疟疾药物，是一种抑制自噬的亲溶酶体试剂。通过对CD44⁺/CD24⁻/低表达的癌症干细胞群体进行计算机基因表达特征分析，氯喹被确定为一种潜在的癌症干细胞抑制剂。自噬在癌细胞适应应激条件中起着关键作用，并且与耐药性和癌症干细胞的维持有关。因此，本研究的目的是检验在三阴性乳腺癌中标准化疗（紫杉醇）添加氯喹（CQ）后潜在的增效作用，并确定氯喹清除三阴性乳腺癌中癌症干细胞的机制。在此，我们报道氯喹通过抑制自噬使三阴性乳腺癌细胞对紫杉醇敏感，并在临床前和临床环境中减少CD44⁺/CD24⁻/低表达的癌症干细胞数量。此外，我们首次报道了一种机制，即氯喹通过降低Janus激活激酶2（Jak2）和DNA甲基转移酶1（DNMT1）的表达，抑制Janus激活激酶2（Jak2） - 信号转导和转录激活因子3（STAT3）信号通路，从而调节三阴性乳腺癌中的癌症干细胞。
Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44+/CD24−/low cancer stem cells (CSC), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an anti-malarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44+/CD24−/low CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus the objectives of this study were to examine the potential enhanced efficacy arising from addition of chloroquine (CQ) to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44+/CD24−/low CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2) - Signal transducer and activator of transcription 3 (STAT3) signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1 (DNMT1).
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影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
DOI：
10.1073/pnas.1006732107
发表时间：
2010-10-19
影响因子：
11.1
作者：
Liu, Huiping;Patel, Manishkumar R.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
15.9
作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
通讯作者：
Calabretta, Bruno
影响因子：
16.8
作者：
Kershaw, Nadia J.;Murphy, James M.;Liau, Nicholas P. D.;Varghese, Leila N.;Laktyushin, Artem;Whitlock, Eden L.;Lucet, Isabelle S.;Nicola, Nicos A.;Babon, Jeffrey J.
通讯作者：
Babon, Jeffrey J.
影响因子：
7.5
作者：
Kenific CM;Thorburn A;Debnath J
通讯作者：
Debnath J