Bcl xL promotes metastasis independent of its anti apoptotic activity
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 TGFb promoter to increase TGFb 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.
Nature communications