p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.
p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.
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DOI：
10.1002/stem.2068
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Chen G
中科院分区：
文献类型：
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作者：
Qi X;Yin N;Ma S;Lepp A;Tang J;Jing W;Johnson B;Dwinell MB;Chitambar CR;Chen G
三阴性乳腺癌（TNBC）是高度进展的，缺乏既定的治疗靶点。p38γ丝裂原活化蛋白激酶（MAPK）（基因名称：MAPK12）在TNBC中过度表达，但过度表达的p38γ如何导致TNBC尚不清楚。在这里，我们发现p38γ激活通过刺激癌症干细胞（CSC）的扩张来促进TNBC的发展和进展，并可能作为一种新的治疗靶点。TNBC细胞中p38γ沉默可减少乳腺球形成，降低CSC驱动因子Nanog、Oct3/4和Sox2的表达水平。此外，p38γ mapk强迫表达本身就足以刺激CSC扩增并诱导上皮细胞在体外和体内转化。此外，p38γ依赖于其刺激CSC扩张和乳腺癌进展的活性，表明应用其药理抑制剂有治疗机会。事实上，无毒的p38γ特异性药物抑制剂吡非尼酮在体外和/或体内选择性地抑制TNBC的生长，并显著减少CSC的数量。从机制上讲，p38γ通过多蛋白复合物的形成，通过c-Jun/AP-1刺激Nanog转录。这些结果共同表明p38γ可以驱动TNBC的发展和进展，并可能通过刺激CSC扩张成为TNBC的新治疗靶点。用吡非尼酮抑制p38γ活性可能是治疗TNBC的新策略。
Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38γ mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38γ contributes to TNBC remains unknown. Here we show that p38γ activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38γ silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38γ MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38γ depends on its activity to stimulate CSC expansion and breast cancer progression, indicating a therapeutic opportunity by application of its pharmacological inhibitor. Indeed, the non-toxic p38γ specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38γ stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38γ can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38γ activity with pirfenidone may be a novel strategy for the treatment of TNBC.