Bcl-xL promotes metastasis independent of its anti-apoptotic activity

Soyoung Choi, Zhengming Chen, Laura H. Tang, Yuanzhang Fang, Sandra J. Shin, Nicole C. Panarelli, Yao-Tseng Chen, Yi Li, Xuejun Jiang and Yi-Chieh Nancy Du ()
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Soyoung Choi: Weill Cornell Medicine
Zhengming Chen: Weill Cornell Medicine
Laura H. Tang: Memorial Sloan Kettering Cancer Center
Yuanzhang Fang: Lester and Sue Smith Breast Center, Baylor College of Medicine
Sandra J. Shin: Weill Cornell Medicine
Nicole C. Panarelli: Weill Cornell Medicine
Yao-Tseng Chen: Weill Cornell Medicine
Yi Li: Lester and Sue Smith Breast Center, Baylor College of Medicine
Xuejun Jiang: Cell Biology Program, Memorial Sloan Kettering Cancer Center
Yi-Chieh Nancy Du: Weill Cornell Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10384

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