Bcl-xL promotes metastasis independent of its anti-apoptotic activity.
Bcl-xL promotes metastasis independent of its anti-apoptotic activity.
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DOI：
10.1038/ncomms10384
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发表时间：
2016-01-20
影响因子：
16.6
通讯作者：
Du YN
中科院分区：
文献类型：
--
作者：
Choi S;Chen Z;Tang LH;Fang Y;Shin SJ;Panarelli NC;Chen YT;Li Y;Jiang X;Du YN
Bcl-xL抑制线粒体介导的细胞凋亡，在癌症中经常过表达以促进癌细胞存活。Bcl-xL也促进转移。然而，目前尚不清楚这种转移功能是否依赖于其在线粒体中的抗凋亡活性。在这里，我们证明Bcl-xL促进转移独立于其抗凋亡活性。我们发现凋亡缺陷的Bcl-xL突变体和靶向细胞核的工程化Bcl-xL促进胰腺神经内分泌肿瘤（panNET）和乳腺癌细胞系的上皮-间质转化、迁移、侵袭和干细胞化。然而，靶向线粒体或核外的Bcl-xL蛋白不具有这些功能。我们在自发和异种移植小鼠模型中证实了我们的发现。此外，Bcl-xL通过表观遗传修饰tgf - β启动子来增加tgf - β信号传导，从而发挥转移功能。与这些发现一致，我们在人类转移性panNETs中检测到核Bcl-xL。综上所述，Bcl-xL的转移功能独立于其抗凋亡活性及其在线粒体中的驻留。Bcl-xL是一种抗凋亡蛋白，也与转移有关。在这项研究中，作者发现核Bcl-xL通过调节tgf - β信号通路促进转移，而这与Bcl-xL的抗凋亡活性无关。
Bcl-xL suppresses mitochondria-mediated apoptosis and is frequently overexpressed in cancer to promote cancer cell survival. Bcl-xL also promotes metastasis. However, it is unclear whether this metastatic function is dependent on its anti-apoptotic activity in the mitochondria. Here we demonstrate that Bcl-xL promotes metastasis independent of its anti-apoptotic activity. We show that apoptosis-defective Bcl-xL mutants and an engineered Bcl-xL targeted to the nucleus promote epithelial–mesenchymal transition, migration, invasion and stemness in pancreatic neuroendocrine tumour (panNET) and breast cancer cell lines. However, Bcl-xL proteins targeted to the mitochondria or outside of the nucleus do not have these functions. We confirm our findings in spontaneous and xenograft mouse models. Furthermore, Bcl-xL exerts metastatic function through epigenetic modification of the TGFβ promoter to increase TGFβ signalling. Consistent with these findings, we detect nuclear Bcl-xL in human metastatic panNETs. Taken together, the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence in the mitochondria. Bcl-xL is an anti-apoptotic protein that has also been implicated in metastasis. In this study, the authors show that nuclear Bcl-xL promotes metastasis by regulating TGFβ signaling, which is independent of the anti-apoptotic activity of Bcl-xL.