Inhibition of BMK1 pathway suppresses cancer stem cells through BNIP3 and BNIP3L.
Inhibition of BMK1 pathway suppresses cancer stem cells through BNIP3 and BNIP3L.
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DOI：
10.18632/oncotarget.5337
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Yang Q
中科院分区：
文献类型：
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作者：
Song C;Xu Q;Jiang K;Zhou G;Yu X;Wang L;Zhu Y;Fang L;Yu Z;Lee JD;Yu SC;Yang Q
癌症干细胞（CSC）具有许多与干细胞相关的特征，并被认为是驱动肿瘤发生的动力。尽管靶向肿瘤干细胞为新一代化疗药物提供了巨大的前景，但缺乏有效的药物靶点和合适的药理学试剂严重阻碍了化疗药物的发展。在这里，我们发现BMK 1的磷酸化不仅与胚胎和诱导多能干细胞（iPS）细胞显著相关，而且与CSC也显著相关。结果表明，通过表达MEK 5D激活BMK 1增强了CSC的自我更新（球体形成）、增殖（克隆形成）和致瘤能力。而BMK 1抑制剂XMD 8 -92则抑制了这些能力。RNA-seq和微阵列分析显示，抑制BMK 1显著增强了BNIP 3和BNIP 3L的表达，它们在细胞死亡中起重要作用。进一步的研究表明，shRNA介导的BNIP 3和BNIP 3L的敲低损害了BMK 1抑制剂、XMD 8 -92诱导的CSC球体形成和克隆形成的抑制。这些结果不仅表明BMK 1在维持CSCs的“干性”中起重要作用，而且暗示BMK 1可能是CSCs的潜在药物靶点。
Cancer stem cells (CSCs) possess many characteristics associated with stem cells and are believed to drive tumor initiation. Although targeting of CSCs offers great promise for the new generation of therapeutics, lack of the effective drugable target and appropriate pharmacological reagents significantly impedes the development of chemotherapies. Here, we show that the phosphorylation of BMK1 was significantly correlated with not only embryonic and induced pluripotent stem (iPS) cells, but also the CSCs. It was showed that activation of BMK1 by the expression of MEK5D enhanced the self-renew (sphere formation), proliferation (clone formation) and tumorigenic capacity of CSCs. While BMK1 inhibitor, XMD8-92, suppressed these capacities. RNA-seq and microarray analysis revealed that inhibition of BMK1 significantly enhanced the expression of BNIP3 and BNIP3L, which play important roles in cell death. Further study indicated that shRNA-mediated knock down of BNIP3 and BNIP3L impairs the BMK1 inhibitor, XMD8-92-induced suppression of sphere formation and clone formation of CSC. Collectively, these results not only indicate that BMK1 plays an important role in maintaining “stemness” of CSCs, but also implicate that BMK1 might be a potential drug target for CSCs.